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Aquino A, Franzese O. Reciprocal Modulation of Tumour and Immune Cell Motility: Uncovering Dynamic Interplays and Therapeutic Approaches. Cancers (Basel) 2025; 17:1547. [PMID: 40361472 PMCID: PMC12072109 DOI: 10.3390/cancers17091547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.
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Affiliation(s)
| | - Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
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Cui M, Zhou M, Zhou L, Zhou G, Liu Y. Tertiary lymphoid structures achieve 'cold' to 'hot' transition by remodeling the cold tumor microenvironment. Biochim Biophys Acta Rev Cancer 2025; 1880:189312. [PMID: 40189114 DOI: 10.1016/j.bbcan.2025.189312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 03/30/2025] [Accepted: 03/31/2025] [Indexed: 04/10/2025]
Abstract
Immune checkpoint blockade (ICB) therapies have demonstrated significant clinical efficacy in immune-infiltrated tumors such as melanoma and non-small cell lung cancer. However, "cold tumors"-including ovarian cancer, pancreatic cancer, and gliomas-exhibit insufficient immune infiltration, leading to poor therapeutic responses to ICBs and limited improvement in patient prognosis. Recent studies have shown that tumor-associated tertiary lymphoid structures (TLSs) can induce strong local immune responses within the tumor microenvironment (TME), serving as important biological markers for predicting ICB therapy efficacy. Notably, preclinical and clinical studies on cold tumors have confirmed that TLSs can potently enhance ICB efficacy through TME remodeling-a breakthrough that has attracted considerable attention. Here, we systematically examine the immunological profile of cold tumors and decipher the mechanistic basis for their impaired immune cell infiltration. We further delineate the distinctive features of tumor-associated TLSs in generating antitumor immunity and establish criteria for their identification. Significantly, we emphasize the unique capability of TLSs to reprogram the immunosuppressive tumor microenvironment characteristic of cold tumors. Based on these insights, we evaluate clinical evidence supporting TLS-mediated enhancement of ICB efficacy and discuss emerging strategies for exogenous TLSs induction.
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Affiliation(s)
- Mengke Cui
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road Changsha, 410008, PR China; National Laboratory of Medical Genetics, Central South University, Changsha 410078, PR China
| | - Mengfan Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road Changsha, 410008, PR China; National Laboratory of Medical Genetics, Central South University, Changsha 410078, PR China
| | - Lu Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road Changsha, 410008, PR China; National Laboratory of Medical Genetics, Central South University, Changsha 410078, PR China
| | - Gan Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road Changsha, 410008, PR China; National Laboratory of Medical Genetics, Central South University, Changsha 410078, PR China; National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, Hunan 410008, PR China.
| | - Yingzi Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road Changsha, 410008, PR China; National Laboratory of Medical Genetics, Central South University, Changsha 410078, PR China.
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3
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Moon CY, Belabed M, Park MD, Mattiuz R, Puleston D, Merad M. Dendritic cell maturation in cancer. Nat Rev Cancer 2025; 25:225-248. [PMID: 39920276 PMCID: PMC11954679 DOI: 10.1038/s41568-024-00787-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2024] [Indexed: 02/09/2025]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that are present at low abundance in the circulation and tissues; they serve as crucial immune sentinels by continually sampling their environment, migrating to secondary lymphoid organs and shaping adaptive immune responses through antigen presentation. Owing to their ability to orchestrate tolerogenic or immunogenic responses to a specific antigen, DCs have a pivotal role in antitumour immunity and the response to immune checkpoint blockade and other immunotherapeutic approaches. The multifaceted functions of DCs are acquired through a complex, multistage process called maturation. Although the role of inflammatory triggers in driving DC maturation was established decades ago, less is known about DC maturation in non-inflammatory contexts, such as during homeostasis and in cancer. The advent of single-cell technologies has enabled an unbiased, high-dimensional characterization of various DC states, including mature DCs. This approach has clarified the molecular programmes associated with DC maturation and also revealed how cancers exploit these pathways to subvert immune surveillance. In this Review, we discuss the mechanisms by which cancer disrupts DC maturation and highlight emerging therapeutic opportunities to modulate DC states. These insights could inform the development of DC-centric immunotherapies, expanding the arsenal of strategies to enhance antitumour immunity.
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Affiliation(s)
- Chang Yoon Moon
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Meriem Belabed
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew D Park
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raphaël Mattiuz
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Puleston
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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4
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Du B, Geng J, Wu B, Wang H, Luo R, Liu H, Zhang R, Shan F, Liu L, Zhang S. Pipelines for lymphocyte homeostasis maintenance during cancer immunotherapy. Front Immunol 2025; 16:1522417. [PMID: 40196122 PMCID: PMC11973195 DOI: 10.3389/fimmu.2025.1522417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/27/2025] [Indexed: 04/09/2025] Open
Abstract
In general, increasing lymphocyte entry into tumor microenvironment (TME) and limiting their efflux will have a positive effect on the efficacy of immunotherapy. Current studies suggest maintenance lymphocyte homeostasis during cancer immunotherapy through the two pipelines tumor-associated high endothelial venules and lymphatic vessels. Tumor-associated high endothelial venules (TA-HEVs) play a key role in cancer immunotherapy through facilitating lymphocyte trafficking to the tumor. While tumor-associated lymphatic vessels, in contrast, may promote the egress of lymphocytes and restrict their function. Therefore, the two traffic control points might be potential to maintain lymphocyte homeostasis in cancer during immunotherapy. Herein, we highlight the unexpected roles of lymphocyte circulation regulated by the two gateways for through reviewing the biological characters and functions of TA-HEVs and tumor-associated lymphatic vessels in the entry, positioning and exit of lymphocyte cells in TME during anti-tumor immunity.
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Affiliation(s)
- Bensu Du
- China Medical University, Shenyang, China
| | - Jin Geng
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, China
| | - Bin Wu
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Houru Wang
- Northeast Yucai Foreign Language School, Shenyang, China
| | - Ru Luo
- Jinzhou Medical University, Jinzhou, China
| | | | - Rui Zhang
- China Medical University, Shenyang, China
| | - Fengping Shan
- Department of Immunology, School of Basic Medical Science, China Medical University, Shenyang, China
| | - Lei Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuling Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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Westbom-Fremer S, Tran L, Ebbesson A, Martin de la Fuente L, Jönsson JM, Kannisto P, Veerla S, Hedenfalk I. Tertiary lymphoid structures in high-grade serous tubo-ovarian carcinoma: anatomical site matters. Cancer Immunol Immunother 2025; 74:56. [PMID: 39751944 PMCID: PMC11699021 DOI: 10.1007/s00262-024-03911-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/29/2024] [Indexed: 01/04/2025]
Abstract
Tertiary lymphoid structures (TLS) in the tumor microenvironment are prognostically beneficial in many solid cancer types. Reports on TLS in high-grade serous tubo-ovarian carcinoma (HGSC) are few, and the prognostic impact is unclear. We investigated mature TLS (mTLS), immature TLS (iTLS) and lymphoid aggregates (LA) in primary adnexal tumors (PTs) and synchronous omental/peritoneal metastases (pMets) of HGSC. Whole H&E slides were scrutinized for mTLS and LA in a population-based cohort of 130 cases with stage III-IV HGSC. The immune cell tumor infiltration was evaluated with single chromogenic immunohistochemistry (IHC) on a tissue microarray (TMA) from the same cases. Selected whole slides (PT n = 11, pMet n = 10) of the cases most abundant in mTLS and LA were further investigated with multiplex IHC and immunofluorescence using digital image analysis (QuPath), to confirm TLS status and map the T and B lymphocyte subtypes. The results showed that mTLS were more common in pMets than in PTs but did not have an independent prognostic impact on overall or progression-free survival. The presence of mTLS correlated with intratumoral infiltration of CD8+ cytotoxic T cells, FOXP3+ regulatory T cells and PD-1+ lymphocytes in pMets only. Although overall mTLS cell composition was similar between PTs and pMets, the outer zones of mTLS in PTs were more immune cell-rich. In conclusion, our results indicate differences in TLS presence and cellular elements between primary adnexal tumors and synchronous peritoneal metastases, which are important to consider when conducting studies of the immune environment in HGSC.
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Affiliation(s)
- Sofia Westbom-Fremer
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden.
| | - Lena Tran
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Anna Ebbesson
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Laura Martin de la Fuente
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Jenny-Maria Jönsson
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Päivi Kannisto
- Division of Obstetrics and Gynaecology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Srinivas Veerla
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Ingrid Hedenfalk
- Division of Oncology, Department of Clinical Sciences Lund, and Lund University Cancer Center, Lund University, Lund, Sweden
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6
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Molina-García M, Rojas-Lechuga MJ, Torres Moral T, Bagué J, Mateu J, Langdon C, Lop J, Gonçalves de Souza V, Alós L, López-Chacón M, Podlipnik S, Carrera C, Malvehy J, Alobid I, da Silva-Júnior RMP, Puig S. Distinct Transcriptomic and Tumor Microenvironment Profiles in Sinonasal Mucosal Melanoma and Aggressive Cutaneous Melanomas. Cancers (Basel) 2024; 16:4172. [PMID: 39766071 PMCID: PMC11674703 DOI: 10.3390/cancers16244172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Sinonasal mucosal melanoma (SNMM) is a rare and aggressive melanoma subtype with a notably poor prognosis compared to cutaneous melanoma (CM). Despite advances in molecular characterization, SNMM remains underexplored, posing a clinical challenge and highlighting the need for detailed molecular profiling. This study aimed to identify the molecular features of SNMM, elucidate its clinical behavior and prognostic implications, and provide insights for improved therapeutic strategies. Methods: This retrospective study analyzed 37 primary melanoma tumors diagnosed at the Hospital Clinic of Barcelona. Gene expression was examined using 1402 immuno-oncology-related probes through next-generation sequencing. Hierarchical clustering analysis (HCA), differentially expressed genes (DEGs), gene set enrichment analysis (GSEA), and the xCell algorithm were performed. The statistical methods comprised descriptive statistics, clinical variable associations, and survival analyses. Results: HCA revealed two primary clusters. Cluster A exclusively contained CM tumors (20/24), while cluster B included all SNMMs (13/13) and some CMs (4/24). Cluster B showed a higher average age at diagnosis (p = 0.018), higher mitotic index (p = 0.0478), fewer BRAF mutations (p = 0.0017), and poorer melanoma-specific survival (p = 0.0029). Cluster B showed 602 DEGs with cell cycle pathways enriched, immune pathways diminished, lower immune scores (p < 0.0001), and higher stromal scores (p = 0.0074). Conclusions: This study revealed distinct molecular characteristics and an altered tumor microenvironment in SNMMs and certain aggressive CMs. Identifying specific genes and pathways involved in cell cycle progression and immune evasion suggests potential prognostic markers, offering new avenues for enhancing treatment strategies and improving patient survival rates.
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Affiliation(s)
- Manuel Molina-García
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
| | - María Jesús Rojas-Lechuga
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Otorhinolaryngology Department, Hospital Clínic de Barcelona, CIBERES, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Teresa Torres Moral
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
- Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Barcelona, Spain
| | - Jaume Bagué
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
| | - Judit Mateu
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
| | - Cristóbal Langdon
- Otorhinolaryngology Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
| | - Joan Lop
- Pathology Department, Hospital Clínic de Barcelona, IDIBAPS, 08036 Barcelona, Spain
| | | | - Llúcia Alós
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- Pathology Department, Hospital Clínic de Barcelona, IDIBAPS, 08036 Barcelona, Spain
| | - Mauricio López-Chacón
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Otorhinolaryngology Department, Hospital Clínic de Barcelona, CIBERES, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Sebastian Podlipnik
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
| | - Cristina Carrera
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
- Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Barcelona, Spain
| | - Josep Malvehy
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
- Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Barcelona, Spain
| | - Isam Alobid
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Otorhinolaryngology Department, Hospital Clínic de Barcelona, CIBERES, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Rui Milton Patricio da Silva-Júnior
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
| | - Susana Puig
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-G.); (R.M.P.d.S.-J.)
- University of Barcelona (UB), 08036 Barcelona, Spain;
- Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
- Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Barcelona, Spain
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Lv J, Zhang X, Zhou M, Yan J, Chao G, Zhang S. Tertiary lymphoid structures in colorectal cancer. Ann Med 2024; 56:2400314. [PMID: 39575712 PMCID: PMC11616745 DOI: 10.1080/07853890.2024.2400314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/23/2024] [Accepted: 08/28/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Tertiary lymphoid structures (TLS) are ectopic clusters of immune cells found in non-lymphoid tissues, particularly within the tumor microenvironment (TME). These structures resemble secondary lymphoid organs and have been identified in various solid tumors, including colorectal cancer (CRC), where they are associated with favorable prognosis. The role of TLS in modulating the immune response within the TME and their impact on cancer prognosis has garnered increasing attention in recent years. OBJECTIVE This review aims to summarize the current understanding of TLS in CRC, focusing on their formation, function, and potential as prognostic markers and therapeutic targets. We explore the mechanisms by which TLS influence the immune response within the TME and their correlation with clinical outcomes in CRC patients. METHODS We conducted a comprehensive review of recent studies that investigated the presence and role of TLS in CRC. The review includes data from histopathological analyses, immunohistochemical studies, and clinical trials, examining the association between TLS density, composition, and CRC prognosis. Additionally, we explored emerging therapeutic strategies targeting TLS formation and function within the TME. RESULTS The presence of TLS in CRC is generally associated with an improved prognosis, particularly in early-stage disease. TLS formation is driven by chronic inflammation and is characterized by the organization of B and T cell zones, high endothelial venules (HEVs), and follicular dendritic cells (FDCs). The density and maturity of TLS are linked to better patient outcomes, including reduced recurrence rates and increased survival. Furthermore, the interplay between TLS and immune checkpoint inhibitors (ICIs) suggests potential therapeutic implications for enhancing anti-tumor immunity in CRC. CONCLUSIONS TLS represent a significant prognostic marker in CRC, with their presence correlating with favorable clinical outcomes. Ongoing research is required to fully understand the mechanisms by which TLS modulate the immune response within the TME and to develop effective therapies that harness their potential. The integration of TLS-focused strategies in CRC treatment could lead to improved patient management and outcomes.
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Affiliation(s)
- Jianyu Lv
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Zhejiang, China
| | - Xiuyu Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Zhejiang, China
| | - Mi Zhou
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Zhejiang, China
| | - Junbin Yan
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Zhejiang, China
| | - Guanqun Chao
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University, China
| | - Shuo Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Zhejiang, China
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8
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Zhang J, Huang Y, Tan X, Wang Z, Cheng R, Zhang S, Chen Y, Jiang F, Tan W, Deng X, Li F. Integrated analysis of multiple transcriptomic approaches and machine learning integration algorithms reveals high endothelial venules as a prognostic immune-related biomarker in bladder cancer. Int Immunopharmacol 2024; 136:112184. [PMID: 38824904 DOI: 10.1016/j.intimp.2024.112184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/19/2024] [Accepted: 04/28/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND Despite the availability of established surgical and chemotherapy options, the treatment of bladder cancer (BCa) patients remains challenging. While immunotherapy has emerged as a promising approach, its benefits are limited to a subset of patients. The exploration of additional targets to enhance the efficacy of immunotherapy is a valuable research direction. METHOD High endothelial venules (HEV) ssGSEA analysis was conducted using BEST. Through the utilization of R packages Limma, Seurat, SingleR, and Harmony, analyses were performed on spatial transcriptomics, bulk RNA-sequencing (bulk RNA-seq), and single-cell RNA sequencing (scRNA-seq) data, yielding HEV-related genes (HEV.RGs). Molecular subtyping analysis based on HEV.RGs was conducted using R package MOVICS, and various machine learning-integrated algorithm was employed to construct prognostic model. LDLRAD3 was validated through subcutaneous tumor formation in mice, HEV induction, Western blot, and qPCR. RESULTS A correlation between higher HEV levels and improved immune response and prognosis was revealed by HEV ssGSEA analysis in BCa patients receiving immunotherapy. HEV.RGs were identified in subsequent transcriptomic analyses. Based on these genes, BCa patients were stratified into two molecular clusters with distinct survival and immune infiltration patterns using various clustering-integrated algorithm. Prognostic model was developed using multiple machine learning-integrated algorithm. Low LDLRAD3 expression may promote HEV generation, leading to enhanced immunotherapy efficacy, as suggested by bulk RNA-seq, scRNA-seq analyses, and experimental validation of LDLRAD3. CONCLUSIONS HEV served as a predictive factor for immune response and prognosis in BCa patients receiving immunotherapy. LDLRAD3 represented a potential target for HEV induction and enhancing the efficacy of immunotherapy.
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Affiliation(s)
- Jinge Zhang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Yuan Huang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Xing Tan
- Department of Nanfang Hospital Administration Office, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Zihuan Wang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Ranyang Cheng
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Shenlan Zhang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Yuwen Chen
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Feifan Jiang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Wanlong Tan
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China.
| | - Xiaolin Deng
- Department of Urology, Ganzhou People's Hospital, Ganzhou, PR China.
| | - Fei Li
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China.
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Wang B, Han Y, Liu J, Zhang X, Deng Y, Jiang Y. Intratumoral high endothelial venules in solid tumors: a pooled study. Front Immunol 2024; 15:1401118. [PMID: 39040120 PMCID: PMC11260642 DOI: 10.3389/fimmu.2024.1401118] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Objective We performed this pooled analysis for the first time to comprehensively explore the prognostic value of tumor-associated high endothelial venules (TA-HEVs) and determine their relationships with clinicopathological features in solid tumors. Methods Four online databases, including PubMed, Web of Science, Embase, and Cochrane Library, were comprehensively searched to identify studies assessing the effect of TA-HEVs on prognosis or clinicopathological features. Hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate survival outcomes, including overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS). The association between TA-HEV status and clinicopathological characteristics was assessed by odds ratios (ORs) combined with 95% CIs. Subgroup analysis was conducted to explore sources of heterogeneity. The sensitivity analysis was performed to evaluate the stability of our findings. Meanwhile, Funnel plots were employed to visually evaluate potential publication bias, and both Begg's and Egger's tests were adopted to quantitatively determine publication bias. Results A total of 13 retrospective cohort studies, involving 1,933 patients were finally included in this meta-analysis. Effect-size pooling analysis showed that the positivity of TA-HEVs was related to improved OS (pooled HR: 0.75, 95% CI: 0.62-0.93, P<0.01), and DFS (pooled HR = 0.54, 95% CI = 0.41-0.72, P< 0.01). However, TA-HEV positivity in solid tumors was not linked to PFS (pooled HR = 0.75, 95% CI 0.34-1.64, P = 0.47) or CSS (pooled HR: 0.58, 95% CI: 0.04-7.58, P= 0.68). Further subgroup analysis demonstrated that ethnicity and source of HR were the main factors contributing to heterogeneity. Moreover, TA-HEVs were inversely associated with lymph node metastasis and distant metastasis, but were positively related to worse tumor differentiation. However, TA-HEVs were not significantly correlated with sex, LVI, clinical stage, and depth of invasion. Sensitivity analysis suggested that the pooled results were stable and reliable, with no significant publication bias in all included articles. Conclusions This is the first comprehensive analysis of the prognostic value of TA-HEVs in solid tumors using existing literature. Overall, our study demonstrated a significant correlation between TA-HEVs and prognosis as well as clinicopathological features. TA-HEVs may serve as novel immune-related biomarkers for clinical assessments and prognosis prediction in solid tumors. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php, identifier CRD42023394998.
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Affiliation(s)
- Bin Wang
- Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yin Han
- Cancer Prevention and Treatment Institute of Chengdu, Department of Pathology, Chengdu Fifth People’s Hospital (The Second Clinical Medical College, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, China
| | - Jie Liu
- Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyao Zhang
- Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yaotiao Deng
- Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Jiang
- Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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10
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Cho YJ, Hwang I, Park S, Lee S, Kang SY, Kim MJ, Ahn S, Kim KM. Prognostic Effect of Tertiary Lymphoid Structures in Epstein-Barr Virus-Associated Gastric Carcinomas Measured by Digital Image Analysis. J Transl Med 2024; 104:102071. [PMID: 38677591 DOI: 10.1016/j.labinv.2024.102071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 02/25/2024] [Accepted: 04/18/2024] [Indexed: 04/29/2024] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is characterized by prominent tumor-infiltrating lymphocytes (TILs) and has a favorable prognosis. Tertiary lymphoid structures (TLS), characterized by ectopic aggregated lymphocytes with high-endothelial venules (HEV), are associated with favorable outcomes in various solid tumors. We hypothesized that EBVaGC, characterized by intense TILs, may be closely associated with TLS or HEV. To test this hypothesis, we digitally analyzed the TLS, HEV, and TILs in 73 surgically resected advanced EBVaGCs. For HEV, dual MECA-79 and CD31 dual immunohistochemistry were performed, and the ectopic expression of MECA-79 in tumor cells was measured. In 73 patients with EBVaGC, a high-TLS ratio was found in 29 (39.7%) cases, high-tumor-associated HEV density in 44 (60.3%) cases, and high-CD8+ TIL density in 38 (52.1%) cases. Ectopic tumor expression of MECA-79 was observed in 36 patients (49.3%) cases. A low-TLS ratio and tumor-associated HEV density were significantly associated with lymph node metastasis (P = .005 and .042, respectively). Ectopic MECA-79 expression was significantly associated with lymph node metastasis (P = .003). Patients with a low-TLS ratio (P = .038), low-HEV density (P = .042), and ectopic tumor MECA-79 expression (P = .032) had significantly worse prognoses. In conclusion, TLS ratio and HEV density affect the survival of patients with EBVaGC and may be related to the immune response that interrupts lymph node metastasis.
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Affiliation(s)
- Yun Joo Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Inwoo Hwang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Suho Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Somin Lee
- Center for Companion Diagnostics, Precision Medicine Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min-Ji Kim
- Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Center for Companion Diagnostics, Precision Medicine Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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11
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Merali N, Jessel MD, Arbe-Barnes EH, Ruby Lee WY, Gismondi M, Chouari T, O'Brien JW, Patel B, Osei-Bordom D, Rockall TA, Sivakumar S, Annels N, Frampton AE. Impact of tertiary lymphoid structures on prognosis and therapeutic response in pancreatic ductal adenocarcinoma. HPB (Oxford) 2024; 26:873-894. [PMID: 38729813 DOI: 10.1016/j.hpb.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/27/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is known to have a heterogeneous desmoplastic tumour microenvironment (TME) with a large number of immunosuppressive cells. Recently, high B-cell infiltration in PDAC has received growing interest as a potential therapeutic target. METHODS Our literature review summarises the characteristics of tumour-associated tertiary lymphoid structures (TLSs) and highlight the key studies exploring the clinical outcomes of TLSs in PDAC patients and the direct effect on the TME. RESULTS The location, density and maturity stages of TLSs within tumours play a key role in determining the prognosis and is a new emerging target in cancer immunotherapy. DISCUSSION TLS development is imperative to improve the prognosis of PDAC patients. In the future, studying the genetics and immune characteristics of tumour infiltrating B cells and TLSs may lead towards enhancing adaptive immunity in PDAC and designing personalised therapies.
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Affiliation(s)
- Nabeel Merali
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, UK; Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK; Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK
| | - Maria-Danae Jessel
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, UK
| | - Edward H Arbe-Barnes
- UCL Institute of Immunity and Transplantation, The Pears Building, Pond Street, London, UK
| | - Wing Yu Ruby Lee
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
| | - Martha Gismondi
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK
| | - Tarak Chouari
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, UK; Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK
| | - James W O'Brien
- Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK
| | - Bhavik Patel
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, UK; Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK; Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK
| | - Daniel Osei-Bordom
- Liver and Digestive Health, University College London, Royal Free Hospital, Pond St, London, UK
| | - Timothy A Rockall
- Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK
| | - Shivan Sivakumar
- Oncology Department and Institute of Immunology and Immunotherapy, Birmingham Medical School, University of Birmingham, Birmingham, UK
| | - Nicola Annels
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, UK
| | - Adam E Frampton
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, UK; Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK; Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK.
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12
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Sussman TA, Severgnini M, Giobbie-Hurder A, Friedlander P, Swanson SJ, Jaklitsch M, Clancy T, Goguen LA, Lautz D, Swanson R, Daley H, Ritz J, Dranoff G, Hodi FS. Phase II trial of vaccination with autologous, irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor in patients with stage III and IV melanoma. Front Oncol 2024; 14:1395978. [PMID: 38812776 PMCID: PMC11133610 DOI: 10.3389/fonc.2024.1395978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/16/2024] [Indexed: 05/31/2024] Open
Abstract
Background In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). The safety, efficacy and anti-tumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation. Methods In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x106, 4x106, or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients. Results GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit. Conclusions Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed.
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Affiliation(s)
- Tamara A. Sussman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Mariano Severgnini
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Clinical Sciences, Curis, Inc., Lexington, MA, United States
| | - Anita Giobbie-Hurder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Division of Biostatistics, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Philip Friedlander
- Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott J. Swanson
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Michael Jaklitsch
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Thomas Clancy
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Laura A. Goguen
- Division of Otolaryngology, Brigham and Women’s Hospital, Boston, MA, United States
| | - David Lautz
- Department of Surgery, Emerson Hospital, Concord, MA, United States
| | - Richard Swanson
- Department of Surgery, UMass Chan Medical School, Worcester, MA, United States
| | - Heather Daley
- Connell and O’Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Jerome Ritz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Connell and O’Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Glenn Dranoff
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - F. Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medical Oncology, Parker Institute for Cancer Immunotherapy, Dana-Farber Cancer Institute, Boston, MA, United States
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13
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Kasikova L, Rakova J, Hensler M, Lanickova T, Tomankova J, Pasulka J, Drozenova J, Mojzisova K, Fialova A, Vosahlikova S, Laco J, Ryska A, Dundr P, Kocian R, Brtnicky T, Skapa P, Capkova L, Kovar M, Prochazka J, Praznovec I, Koblizek V, Taskova A, Tanaka H, Lischke R, Mendez FC, Vachtenheim J, Heinzelmann-Schwarz V, Jacob F, McNeish IA, Halaska MJ, Rob L, Cibula D, Orsulic S, Galluzzi L, Spisek R, Fucikova J. Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer. Nat Commun 2024; 15:2528. [PMID: 38514660 PMCID: PMC10957872 DOI: 10.1038/s41467-024-46873-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 03/13/2024] [Indexed: 03/23/2024] Open
Abstract
Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.
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Affiliation(s)
| | | | | | - Tereza Lanickova
- Sotio Biotech a.s., Prague, Czech Republic
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | | | | | - Jana Drozenova
- Department of Pathology, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | | | | | | | - Jan Laco
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Ales Ryska
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Pavel Dundr
- Department of Pathology, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Roman Kocian
- Department of Gynaecology, Obstetrics and Neonatology, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Tomas Brtnicky
- Department of Gynecology and Obstetrics, 1st Faculty of Medicine, Charles University, University Hospital Bulovka, Prague, Czech Republic
| | - Petr Skapa
- Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Linda Capkova
- Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Marek Kovar
- Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Prochazka
- Czech Center for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Ivan Praznovec
- Department of Gynecology and Obstetrics, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Vladimir Koblizek
- Department of Pneumology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Alice Taskova
- Department of Thoracic Surgery, Charles University, 3rd Faculty of Medicine and Thomayer University Hospital, Prague, Czech Republic
| | - Hisashi Tanaka
- Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, West Hollywood, CA, USA
| | - Robert Lischke
- 3rd Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Fernando Casas Mendez
- Oncology and Pneumology Department, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Jiri Vachtenheim
- 3rd Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Viola Heinzelmann-Schwarz
- Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Francis Jacob
- Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Iain A McNeish
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Michal J Halaska
- Department of Gynecology and Obstetrics, Charles University, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Lukas Rob
- Department of Gynecology and Obstetrics, Charles University, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - David Cibula
- Department of Gynaecology, Obstetrics and Neonatology, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Sandra Orsulic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Radek Spisek
- Sotio Biotech a.s., Prague, Czech Republic
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Jitka Fucikova
- Sotio Biotech a.s., Prague, Czech Republic.
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
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14
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Stolfo JB, Motta ACDA. Density of high endothelial venules and PDL-1 expression: relationship with tumor-infiltrating lymphocytes in primary cutaneous melanomas. AN ACAD BRAS CIENC 2024; 96:e20230441. [PMID: 38511744 DOI: 10.1590/0001-3765202420230441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 07/17/2023] [Indexed: 03/22/2024] Open
Abstract
Studies have highlighted melanoma immunogenicity, and the prognostic importance of tumor infiltrating lymphocytes (TILs) and mechanisms of tumor immune evasion, such as hyperexpression of programmed cell death ligand 1 (PDL-1). High endothelial venules (HEV) are specialized blood vessels that can facilitate the lymphocytes migration to the tumor. Here we evaluate the association of HEV density and PDL-1 expression in primary cutaneous melanomas with the presence and degree of TILs and with other clinicopathological variables (age, sex, tumor location, melanoma histological type, Breslow thickness, ulceration, regression signs, mitotic index). HEV density and PDL-1 expression were assessed immunohistochemically in 78 melanoma cases, using a specific antibody, and were detected in 59% and 76% of these, respectively. Positive associations were identified between HEV density and PDL-1 expression with the presence and degree of lymphocytic infiltration, melanoma histological type and ulceration presence. No correlation was found between HEV density and PDL-1 expression. Our findings confirm the HEV role in the recruitment and facilitation of lymphocyte transport in cutaneous melanomas, where HEV density is strongly associated with the degree of TILs. Additionally, PDL-1 hyperexpression suggests a possible mechanism of tumor immune evasion, which may lead to inactivation and reduction of the tumor lymphocytes number.
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Affiliation(s)
- Josiane B Stolfo
- Programa de Pós-Graduação em Bioexperimentação, Universidade de Passo Fundo, Escola de Ciências Agrárias, Inovação e Negócios, Campus I, BR 285, Km 171, São José, 99001-970 Passo Fundo, RS, Brazil
| | - Adriana C DA Motta
- Programa de Pós-Graduação em Bioexperimentação, Universidade de Passo Fundo, Escola de Ciências Agrárias, Inovação e Negócios, Campus I, BR 285, Km 171, São José, 99001-970 Passo Fundo, RS, Brazil
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15
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van Rijthoven M, Obahor S, Pagliarulo F, van den Broek M, Schraml P, Moch H, van der Laak J, Ciompi F, Silina K. Multi-resolution deep learning characterizes tertiary lymphoid structures and their prognostic relevance in solid tumors. COMMUNICATIONS MEDICINE 2024; 4:5. [PMID: 38182879 PMCID: PMC10770129 DOI: 10.1038/s43856-023-00421-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 11/30/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND Tertiary lymphoid structures (TLSs) are dense accumulations of lymphocytes in inflamed peripheral tissues, including cancer, and are associated with improved survival and response to immunotherapy in various solid tumors. Histological TLS quantification has been proposed as a novel predictive and prognostic biomarker, but lack of standardized methods of TLS characterization hampers assessment of TLS densities across different patients, diseases, and clinical centers. METHODS We introduce an approach based on HookNet-TLS, a multi-resolution deep learning model, for automated and unbiased TLS quantification and identification of germinal centers in routine hematoxylin and eosin stained digital pathology slides. We developed HookNet-TLS using n = 1019 manually annotated TCGA slides from clear cell renal cell carcinoma, muscle-invasive bladder cancer, and lung squamous cell carcinoma. RESULTS Here we show that HookNet-TLS automates TLS quantification across multiple cancer types achieving human-level performance and demonstrates prognostic associations similar to visual assessment. CONCLUSIONS HookNet-TLS has the potential to be used as a tool for objective quantification of TLS in routine H&E digital pathology slides. We make HookNet-TLS publicly available to promote its use in research.
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Affiliation(s)
- Mart van Rijthoven
- Pathology Department, Radboud University Medical Center, Nijmegen, Netherlands.
| | - Simon Obahor
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Fabio Pagliarulo
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | | | - Peter Schraml
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Jeroen van der Laak
- Pathology Department, Radboud University Medical Center, Nijmegen, Netherlands
| | - Francesco Ciompi
- Pathology Department, Radboud University Medical Center, Nijmegen, Netherlands
| | - Karina Silina
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland
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16
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Zhan Z, Shi-jin L, Yi-ran Z, Zhi-long L, Xiao-xu Z, Hui D, Pan YL, Pan JH. High endothelial venules proportion in tertiary lymphoid structure is a prognostic marker and correlated with anti-tumor immune microenvironment in colorectal cancer. Ann Med 2023; 55:114-126. [PMID: 36503344 PMCID: PMC9754014 DOI: 10.1080/07853890.2022.2153911] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 11/27/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND High endothelial venules (HEV) and tertiary lymphoid structures (TLS) are associated with clinical outcomes of patients with colorectal cancer (CRC). However, because HEV are components of TLS, there have been few studies of the role of the HEV proportion in TLS (HEV/TLS). This study investigated the role of the HEV/TLS and its relationship with the tumor immune microenvironment in CRC. METHODS A retrospective analysis of 203 cases of tissue pathologically diagnosed as CRC after general surgery was performed at the First Affiliated Hospital of Jinan University from January 2014 to July 2017. Paraffin sections were obtained from the paracancerous intestinal mucosal tissues. The area of HEV and TLS and immune cells were detected by immunohistochemistry. We further divided the positive HEV expression group into the high HEV/TLS group and the low HEV/TLS group by the average area of HEV/TLS. After grouping, the data were also analyzed using the chi-square test, Kaplan-Meier method, and univariate and multivariate Cox proportional risk regression analyses. A correlation analysis of the HEV/TLS and immune cells as well as angiogenesis was performed. RESULTS Patients with a high HEV/TLS in CRC tissue were associated with longer OS, DFS and lower TNM stage. Meanwhile, CRC tissue with a high HEV/TLS showed a greater ability to recruit the CD3+ T cells, CD8+ T cells and M1 macrophages and correlated with less angiogenesis. Conclusively, high HEV/TLS links to the favorable prognosis of CRC patients and correlated with anti-tumor immune microenvironment, which can be a potential biomarker for prognosis of CRC patients. CONCLUSION A high HEV/TLS is associated with a favorable prognosis for CRC and is correlated with the anti-tumor immune microenvironment. Therefore, it is a potential biomarker of the CRC prognosis.KEY MESSAGESHigh HEV/TLS is associated with a favorable prognosis for CRC.High HEV/TLS correlated with the anti-tumor immune microenvironment of CRC and can serve as a novel prognostic biomarker.
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Affiliation(s)
- Zhao Zhan
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liu Shi-jin
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhang Yi-ran
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liu Zhi-long
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhao Xiao-xu
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ding Hui
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yun-long Pan
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jing-hua Pan
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
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Suman S, Markovic SN. Melanoma-derived mediators can foster the premetastatic niche: crossroad to lymphatic metastasis. Trends Immunol 2023; 44:724-743. [PMID: 37573226 PMCID: PMC10528107 DOI: 10.1016/j.it.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 08/14/2023]
Abstract
The natural history of advanced malignant melanoma demonstrates that, in most cases, widespread tumor dissemination is preceded by regional metastases involving tumor-draining lymph nodes [sentinel lymph nodes (SLNs)]. Under physiological conditions, LNs play a central role in immunosurveillance to non-self-antigens to which they are exposed via afferent lymph. The dysfunctional immunity in SLNs is mediated by tumor secretory factors that allow the survival of metastatic melanoma cells within the LN by creating a premetastatic niche (PMN). Recent studies outline the altered microenvironment of LNs shaped by melanoma mediators. Here, we discuss tumor secretory factors involved in subverting tumor immunity and remodeling LNs and highlight emerging therapeutic strategies to reinvigorate antitumoral immunity in SLNs.
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Affiliation(s)
- Shankar Suman
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Svetomir N Markovic
- Department of Oncology, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA.
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18
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Bravo AI, Aris M, Panouillot M, Porto M, Dieu-Nosjean MC, Teillaud JL, Barrio MM, Mordoh J. HEV-associated dendritic cells are observed in metastatic tumor-draining lymph nodes of cutaneous melanoma patients with longer distant metastasis-free survival after adjuvant immunotherapy. Front Immunol 2023; 14:1231734. [PMID: 37691949 PMCID: PMC10485604 DOI: 10.3389/fimmu.2023.1231734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/07/2023] [Indexed: 09/12/2023] Open
Abstract
Introduction Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic tumor-draining lymph nodes (mTDLN) are the first encounter site between the metastatic CM cells and an organized immune structure. Therefore, their study may reveal mechanisms that could influence patients´ outcomes. Methods Twenty-nine stage-III CM patients enrolled in clinical trials to study the vaccine VACCIMEL were included in this retrospective study. After radical mTDLN dissection, patients were treated with VACCIMEL (n=22) or IFNα-2b (n=6), unless rapid progression (n=1). Distant Metastasis-Free Survival (DMFS) was selected as an end-point. Two cohorts of patients were selected: one with a good outcome (GO) (n=17; median DMFS 130.0 months), and another with a bad outcome (BO) (n=12; median DMFS 8.5 months). We analyzed by immunohistochemistry and immunofluorescence the expression of relevant biomarkers to tumor-cell biology and immune cells and structures in mTDLN, both in the tumor and peritumoral areas. Results In BO patients, highly replicating Ki-67+ tumor cells, low tumor HLA-I expression and abundant FoxP3+ lymphocytes were found (p=0.037; p=0.056 and p=0.021). In GO patients, the most favorable biomarkers for prolonged DMFS were the abundance of peri- and intra-tumoral CD11c+ cells (p=0.0002 and p=0.001), peri-tumoral DC-LAMP+ dendritic cells (DCs) (p=0.001), and PNAd+ High Endothelial Venules (HEVs) (p=0.004). Most strikingly, we describe in GO patients a peculiar, heterogeneous structure that we named FAPS (Favoring Antigen-Presenting Structure), a triad composed of DC, HEV and CD62L+ naïve lymphocytes, whose postulated role would be to favor tumor antigen (Ag) priming of incoming naïve lymphocytes. We also found in GO patients a preferential tumor infiltration of CD8+ and CD20+ lymphocytes (p=0.004 and p=0.027), as well as peritumoral CD20+ aggregates, with no CD21+ follicular dendritic cells detected (p=0.023). Heterogeneous infiltration with CD64+CD68-CD163-, CD64+CD68+CD163- and CD64+CD68+CD163+ macrophages were observed in both cohorts. Discussion The analysis of mTDLN in GO and BO patients revealed marked differences. This work highlights the importance of analyzing resected mTDLN from CM patients and suggests a correlation between tumor and immune characteristics that may be associated with a spontaneous or vaccine-induced long DMFS. These results should be confirmed in prospective studies.
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Affiliation(s)
- Alicia Inés Bravo
- Laboratorio de Cancerología, Fundación Instituto Leloir, Ciudad Autónoma de Buenos Aires (CABA), Argentina
- Unidad de Inmunopatología, Hospital HIGA Eva Perón, Provincia de Buenos Aires, Buenos Aires, Argentina
| | - Mariana Aris
- Centro de Investigaciones Oncológicas, Fundación Cáncer (FUCA), Ciudad Autónoma de Buenos Aires (CABA), Argentina
| | - Marylou Panouillot
- Sorbonne University, Faculty of Medicine, UMRS 1135, Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
- Inserm U.1135, Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
- Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
| | - Martina Porto
- Laboratorio de Cancerología, Fundación Instituto Leloir, Ciudad Autónoma de Buenos Aires (CABA), Argentina
| | - Marie-Caroline Dieu-Nosjean
- Sorbonne University, Faculty of Medicine, UMRS 1135, Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
- Inserm U.1135, Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
- Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
| | - Jean-Luc Teillaud
- Sorbonne University, Faculty of Medicine, UMRS 1135, Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
- Inserm U.1135, Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
- Laboratory “Immune Microenvironment and Immunotherapy”, Centre d’Immunologie et des Maladies Infectieuses (CIMI), Paris, France
| | - María Marcela Barrio
- Centro de Investigaciones Oncológicas, Fundación Cáncer (FUCA), Ciudad Autónoma de Buenos Aires (CABA), Argentina
| | - José Mordoh
- Laboratorio de Cancerología, Fundación Instituto Leloir, Ciudad Autónoma de Buenos Aires (CABA), Argentina
- Centro de Investigaciones Oncológicas, Fundación Cáncer (FUCA), Ciudad Autónoma de Buenos Aires (CABA), Argentina
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Sabahi M, Salehipour A, Bazl MSY, Rezaei N, Mansouri A, Borghei-Razavi H. Local immunotherapy of glioblastoma: A comprehensive review of the concept. J Neuroimmunol 2023; 381:578146. [PMID: 37451079 DOI: 10.1016/j.jneuroim.2023.578146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/24/2023] [Accepted: 07/04/2023] [Indexed: 07/18/2023]
Abstract
Despite advancements in standard treatments, the prognosis of Glioblastoma (GBM) remains poor, prompting research for novel therapies. Immunotherapy is a promising treatment option for GBM, and many immunotherapeutic agents are currently under investigation. Chimeric antigen receptor (CAR) T cells are rapidly evolving in immunotherapy of GBM with many clinical trials showing efficacy of CAR T cells exerting anti-tumor activity following recognition of tumor-associated antigens (TAAs). Exhaustion in CAR T cells can reduce their capacity for long-term persistence and anti-tumor action. Local immunotherapy, which targets the tumor microenvironment and creates a more hospitable immunological environment for CAR T cells, has the potential to reduce CAR T cell exhaustion and increase immunity. Tertiary lymphoid structures (TLS) are ectopic lymphoid-like formations that can develop within the tumor microenvironment or in other non-lymphoid tissues. As a comprehensive local immunotherapy tool, the incorporation of TLS into an implanted biodegradable scaffold has amazing immunotherapeutic potential. The immune response to GBM can be improved even further by strategically inserting a stimulator of interferon genes (STING) agonist into the scaffold. Additionally, the scaffold's addition of glioma stem cells (GSC), which immunotherapeutic approaches may use to target, enhances the removal of cancer cells from their source. Furthermore, it has been demonstrated that GSCs have an impact on TLS formation, which helps to create a favorable tumor microenvironment. Herein, we overview local delivery of a highly specific tandem AND-gate CAR T cell along with above mentioned components. A multifaceted approach that successfully engages the immune system to mount an efficient targeted immune response against GBM is provided by the integration of CAR T cells, TLS, STING agonists, and GSCs within an implantable biodegradable scaffold. This approach offers a promising therapeutic approach for patients with GBM.
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Affiliation(s)
- Mohammadmahdi Sabahi
- Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, FL, USA.
| | - Arash Salehipour
- Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Sajjad Yavari Bazl
- Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Alireza Mansouri
- Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
| | - Hamid Borghei-Razavi
- Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, FL, USA.
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20
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Elewa YHA, Abd Elwakil MM, Harashima H, Mohamed SKA, Zahran MH. Microenvironmental Changes in Mediastinal Fat-associated Lymphoid Clusters and Lungs in Early and Late Stages of Metastatic Lung Cancer Induction. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2023; 29:1228-1243. [PMID: 37749682 DOI: 10.1093/micmic/ozad044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/07/2023] [Accepted: 03/13/2023] [Indexed: 09/27/2023]
Abstract
The prognosis of metastatic lung melanoma (MLM) has been reported to be poor. An increasing number of studies have reported the function of several immune cells in cancer regression. Although the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of inflammatory lung lesions has been previously reported, the association between MLM progression and MFALCs development has remained unexplored. Herein, we compared the microenvironmental changes in the lungs and MFALCs among phosphate-buffered saline (PBS) and cancer groups at early (1 week) and late (2 weeks) stages following the intravenous injection of B16-F10 melanoma cells into C57BL/6 mice. Except for lung CD4+ helper T-cells and Iba1+ macrophage populations of early stage, we observed a significant increase in the proliferating and immune cell (CD20+ B-lymphocytes, CD3+ T-lymphocytes, CD8+ cytotoxic T-cells, CD16+ natural killer (NK) cells populations, area of high endothelial venules, and lung lymphatic vessels in cancer groups at both the stages as compared with the PBS groups. Furthermore, a significant positive correlation was observed between immune cell populations in MFALCs and the lungs (B- and T-lymphocytes, and NK cells in both stages). Collectively, our findings suggest a promising cancer therapeutic strategy via targeting immune cells in MFALCs.
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Affiliation(s)
- Yaser Hosny Ali Elewa
- Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mahmoud M Abd Elwakil
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Sherif Kh A Mohamed
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mahmoud Hosny Zahran
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
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Bruni S, Mercogliano MF, Mauro FL, Cordo Russo RI, Schillaci R. Cancer immune exclusion: breaking the barricade for a successful immunotherapy. Front Oncol 2023; 13:1135456. [PMID: 37284199 PMCID: PMC10239871 DOI: 10.3389/fonc.2023.1135456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion.
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22
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Shamsoon K, Hiraki D, Yoshida K, Takabatake K, Takebe H, Yokozeki K, Horie N, Fujita N, Nasrun NE, Okui T, Nagatsuka H, Abiko Y, Hosoya A, Saito T, Shimo T. The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment. Int J Mol Sci 2023; 24:ijms24108862. [PMID: 37240209 DOI: 10.3390/ijms24108862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/02/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
A crucial regulator in melanoma progression and treatment resistance is tumor microenvironments, and Hedgehog (Hh) signals activated in a tumor bone microenvironment are a potential new therapeutic target. The mechanism of bone destruction by melanomas involving Hh/Gli signaling in such a tumor microenvironment is unknown. Here, we analyzed surgically resected oral malignant melanoma specimens and observed that Sonic Hedgehog, Gli1, and Gli2 were highly expressed in tumor cells, vasculatures, and osteoclasts. We established a tumor bone destruction mouse model by inoculating B16 cells into the bone marrow space of the right tibial metaphysis of 5-week-old female C57BL mice. An intraperitoneal administration of GANT61 (40 mg/kg), a small-molecule inhibitor of Gli1 and Gli2, resulted in significant inhibition of cortical bone destruction, TRAP-positive osteoclasts within the cortical bone, and endomucin-positive tumor vessels. The gene set enrichment analysis suggested that genes involved in apoptosis, angiogenesis, and the PD-L1 expression pathway in cancer were significantly altered by the GANT61 treatment. A flow cytometry analysis revealed that PD-L1 expression was significantly decreased in cells in which late apoptosis was induced by the GANT61 treatment. These results suggest that molecular targeting of Gli1 and Gli2 may release immunosuppression of the tumor bone microenvironment through normalization of abnormal angiogenesis and bone remodeling in advanced melanoma with jaw bone invasion.
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Affiliation(s)
- Karnoon Shamsoon
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
- Division of Clinical Cariology and Endodontology, Department of Oral Rehabilitation, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Daichi Hiraki
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Koki Yoshida
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Hiroaki Takebe
- Division of Histology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Kenji Yokozeki
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Naohiro Horie
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Naomasa Fujita
- Division of Dental Anesthesiology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Nisrina Ekayani Nasrun
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Tatsuo Okui
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Yoshihiro Abiko
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Akihiro Hosoya
- Division of Histology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Takashi Saito
- Division of Clinical Cariology and Endodontology, Department of Oral Rehabilitation, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
| | - Tsuyoshi Shimo
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan
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Wang Z, Shi X, Zhao Y, Zhou J, Zhang S, Wang J, Yu W, Zhang X, Ren X, Zhao H. DC101, an anti-VEGFR2 agent, promotes high-endothelial venule formation and immune infiltration versus SAR131675 and fruquintinib. Biochem Biophys Res Commun 2023; 661:10-20. [PMID: 37084488 DOI: 10.1016/j.bbrc.2023.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 04/08/2023] [Indexed: 04/23/2023]
Abstract
There is an increasing interest in combining immune checkpoint inhibitors (ICIs) with anti-angiogenic drugs to enhance their anti-tumor effects. In this study, three anti-angiogenic agents, DC101 (acting on VEGFR2), SAR131675 (acting on VEGFR3), and fruquintinib (a small-molecule inhibitor acting on multiple targets) were administered to B16F1-OVA-loaded C57BL/6 mice. Immune cells infiltration in the tumor tissues, vascular normalization, and high-endothelial venule (HEV) formation were assessed to provide evidence for drug combination. Both DC101 and fruquintinib significantly slowed the melanoma growth and increased the proportion of CD3+ and CD8+ T cells infiltration compared with SAR131675, of note, the effect of DC101 was more pronounced. Moreover, DC101 and fruquintinib increased the interferon-γ and perforin levels, meanwhile, DC101 increased the granzyme B levels, whereas fruquintinib and SAR131675 did not. Only the fruquintinib-treated group showed decreased regulatory T cells infiltration. We found upregulation of PD-L1 expression in tumor cells and CD45+ immune cells in DC101-treated group as well as upregulation of PD-1 expression on CD3+ T cells. However, fruquintinib only increased PD-L1 expression in tumors. Both DC101 and fruquintinib reduced the proportion of CD31+ vessels, while DC101 increased the ratio of α-SMA +/CD31+ cells and reduced the expression of HIF-1α more than fruquintinib. Moreover, DC101 enhanced the infiltration of dendritic cells and B cells, and local HEV formation. In conclusion, our data indicate that DC101 may be a better choice for the combined clinical application of ICIs and anti-angiogenic agents.
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Affiliation(s)
- Zhe Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Xiuhuan Shi
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Yu Zhao
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Jian Zhou
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Siyuan Zhang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Jiahui Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Xiying Zhang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
| | - Hua Zhao
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
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Raju Paul S, Valiev I, Korek SE, Zyrin V, Shamsutdinova D, Gancharova O, Zaitsev A, Nuzhdina E, Davies DL, Dagogo‐Jack I, Frenkel F, Brown JH, Hess JM, Viet S, Petersen JL, Wright CD, Ott H, Auchincloss HG, Muniappan A, Shioda T, Lanuti M, Davis CM, Ehli EA, Hung YP, Mino‐Kenudson M, Tsiper M, Sluder AE, Reeves PM, Kotlov N, Bagaev A, Ataullakhanov R, Poznansky MC. B cell-dependent subtypes and treatment-based immune correlates to survival in stage 3 and 4 lung adenocarcinomas. FASEB Bioadv 2023; 5:156-170. [PMID: 37020749 PMCID: PMC10068771 DOI: 10.1096/fba.2023-00009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 01/30/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non-small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late-stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA-Seq) with deconvolution of RNA-Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B-cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA-Seq datasets. As previously described by others, pre-treatment expression of intratumoral 12-chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre-treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non-ICI treatments.
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Affiliation(s)
- Susan Raju Paul
- Vaccine and Immunotherapy Center, Massachusetts General HospitalCharlestownMassachusettsUSA
- Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
| | | | - Skylar E. Korek
- Vaccine and Immunotherapy Center, Massachusetts General HospitalCharlestownMassachusettsUSA
- Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | | | | | | | | | | | - Diane L. Davies
- Department of Thoracic SurgeryMassachusetts General HospitalBostonMassachusettsUSA
| | - Ibiayi Dagogo‐Jack
- Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Cancer Center, Massachusetts General HospitalBostonMassachusettsUSA
| | | | | | - Joshua M. Hess
- Vaccine and Immunotherapy Center, Massachusetts General HospitalCharlestownMassachusettsUSA
| | - Sarah Viet
- Avera Institute of Human GeneticsSioux FallsSouth DakotaUSA
| | | | - Cameron D. Wright
- Department of Thoracic SurgeryMassachusetts General HospitalBostonMassachusettsUSA
| | - Harald C. Ott
- Department of Thoracic SurgeryMassachusetts General HospitalBostonMassachusettsUSA
| | - Hugh G. Auchincloss
- Department of Thoracic SurgeryMassachusetts General HospitalBostonMassachusettsUSA
| | - Ashok Muniappan
- Department of Thoracic SurgeryMassachusetts General HospitalBostonMassachusettsUSA
| | - Toshihiro Shioda
- Harvard Medical SchoolBostonMassachusettsUSA
- Cancer Center, Massachusetts General HospitalBostonMassachusettsUSA
| | - Michael Lanuti
- Department of Thoracic SurgeryMassachusetts General HospitalBostonMassachusettsUSA
| | | | - Erik A. Ehli
- Avera Institute of Human GeneticsSioux FallsSouth DakotaUSA
| | - Yin P. Hung
- Harvard Medical SchoolBostonMassachusettsUSA
- Department of PathologyMassachusetts General HospitalBostonMassachusettsUSA
| | - Mari Mino‐Kenudson
- Harvard Medical SchoolBostonMassachusettsUSA
- Cancer Center, Massachusetts General HospitalBostonMassachusettsUSA
- Department of PathologyMassachusetts General HospitalBostonMassachusettsUSA
| | | | - Ann E. Sluder
- Vaccine and Immunotherapy Center, Massachusetts General HospitalCharlestownMassachusettsUSA
- Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Patrick M. Reeves
- Vaccine and Immunotherapy Center, Massachusetts General HospitalCharlestownMassachusettsUSA
- Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
| | | | | | | | - Mark C. Poznansky
- Vaccine and Immunotherapy Center, Massachusetts General HospitalCharlestownMassachusettsUSA
- Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Harvard Medical SchoolBostonMassachusettsUSA
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Vella G, Hua Y, Bergers G. High endothelial venules in cancer: Regulation, function, and therapeutic implication. Cancer Cell 2023; 41:527-545. [PMID: 36827979 DOI: 10.1016/j.ccell.2023.02.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/12/2023] [Accepted: 02/01/2023] [Indexed: 02/25/2023]
Abstract
The lack of sufficient intratumoral CD8+ T lymphocytes is a significant obstacle to effective immunotherapy in cancer. High endothelial venules (HEVs) are organ-specific and specialized postcapillary venules uniquely poised to facilitate the transmigration of lymphocytes to lymph nodes (LNs) and other secondary lymphoid organs (SLOs). HEVs can also form in human and murine cancer (tumor HEVs [TU-HEVs]) and contribute to the generation of diffuse T cell-enriched aggregates or tertiary lymphoid structures (TLSs), which are commonly associated with a good prognosis. Thus, therapeutic induction of TU-HEVs may provide attractive avenues to induce and sustain the efficacy of immunotherapies by overcoming the major restriction of T cell exclusion from the tumor microenvironment. In this review, we provide current insight into the commonalities and discrepancies of HEV formation and regulation in LNs and tumors and discuss the specific function and significance of TU-HEVs in eliciting, predicting, and aiding anti-tumoral immunity.
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Affiliation(s)
- Gerlanda Vella
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Leuven, Belgium
| | - Yichao Hua
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Leuven, Belgium
| | - Gabriele Bergers
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Leuven, Belgium.
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Milutinovic S, Abe J, Jones E, Kelch I, Smart K, Lauder SN, Somerville M, Ware C, Godkin A, Stein JV, Bogle G, Gallimore A. Three-dimensional Imaging Reveals Immune-driven Tumor-associated High Endothelial Venules as a Key Correlate of Tumor Rejection Following Depletion of Regulatory T Cells. CANCER RESEARCH COMMUNICATIONS 2022; 2:1641-1656. [PMID: 36704666 PMCID: PMC7614106 DOI: 10.1158/2767-9764.crc-21-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 06/29/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022]
Abstract
High endothelial venules (HEV) are specialized post capillary venules that recruit naïve T cells and B cells into secondary lymphoid organs (SLO) such as lymph nodes (LN). Expansion of HEV networks in SLOs occurs following immune activation to support development of an effective immune response. In this study, we used a carcinogen-induced model of fibrosarcoma to examine HEV remodeling after depletion of regulatory T cells (Treg). We used light sheet fluorescence microscopy imaging to visualize entire HEV networks, subsequently applying computational tools to enable topological mapping and extraction of numerical descriptors of the networks. While these analyses revealed profound cancer- and immune-driven alterations to HEV networks within LNs, these changes did not identify successful responses to treatment. The presence of HEV networks within tumors did however clearly distinguish responders from nonresponders. Finally, we show that a successful treatment response is dependent on coupling tumor-associated HEV (TA-HEV) development to T-cell activation implying that T-cell activation acts as the trigger for development of TA-HEVs which subsequently serve to amplify the immune response by facilitating extravasation of T cells into the tumor mass.
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Affiliation(s)
- Stefan Milutinovic
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jun Abe
- Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland
| | - Emma Jones
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Inken Kelch
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Kathryn Smart
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Sarah N. Lauder
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michelle Somerville
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Carl Ware
- Laboratory of Molecular Immunology, Sanford Burnham Prebys, La Jolla, California
| | - Andrew Godkin
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jens V. Stein
- Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland
| | - Gib Bogle
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Awen Gallimore
- Systems Immunity University Research Institute, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, United Kingdom
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27
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High endothelial venules associated with better prognosis in esophageal squamous cell carcinoma. Ann Diagn Pathol 2022; 61:152051. [DOI: 10.1016/j.anndiagpath.2022.152051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/26/2022] [Accepted: 10/03/2022] [Indexed: 11/22/2022]
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Michaelides S, Obeck H, Kechur D, Endres S, Kobold S. Migratory Engineering of T Cells for Cancer Therapy. Vaccines (Basel) 2022; 10:1845. [PMID: 36366354 PMCID: PMC9692862 DOI: 10.3390/vaccines10111845] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 10/10/2023] Open
Abstract
Adoptive cell therapy (ACT) and chimeric antigen receptor (CAR) T cell therapy in particular represents an adaptive, yet versatile strategy for cancer treatment. Convincing results in the treatment of hematological malignancies have led to FDA approval for several CAR T cell therapies in defined refractory diseases. In contrast, the treatment of solid tumors with adoptively transferred T cells has not demonstrated convincing efficacy in clinical trials. One of the main reasons for ACT failure in solid tumors is poor trafficking or access of transferred T cells to the tumor site. Tumors employ a variety of mechanisms shielding themselves from immune cell infiltrates, often translating to only fractions of transferred T cells reaching the tumor site. To overcome this bottleneck, extensive efforts are being undertaken at engineering T cells to improve ACT access to solid tumors. In this review, we provide an overview of the immune cell infiltrate in human tumors and the mechanisms tumors employ toward immune exclusion. We will discuss ways in which T cells can be engineered to circumvent these barriers. We give an outlook on ongoing clinical trials targeting immune cell migration to improve ACT and its perspective in solid tumors.
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Affiliation(s)
- Stefanos Michaelides
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80337 Munich, Germany
| | - Hannah Obeck
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80337 Munich, Germany
| | - Daryna Kechur
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80337 Munich, Germany
| | - Stefan Endres
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80337 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80337 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
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29
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Rodriguez AB, Parriott G, Engelhard VH. Tumor necrosis factor receptor regulation of peripheral node addressin biosynthetic components in tumor endothelial cells. Front Immunol 2022; 13:1009306. [PMID: 36189308 PMCID: PMC9520236 DOI: 10.3389/fimmu.2022.1009306] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/26/2022] [Indexed: 11/21/2022] Open
Abstract
Tumor-associated tertiary lymphoid structures are ectopic lymphoid aggregates that have considerable morphological, cellular, and molecular similarity to secondary lymphoid organs, particularly lymph nodes. Tumor vessels expressing peripheral node addressin (PNAd) are hallmark features of these structures. Previous work from our laboratory demonstrated that PNAd is displayed on intratumoral vasculature of murine tumors, and its expression is controlled by the engagement of lymphotoxin-α3, secreted by effector CD8 T cells, with tumor necrosis factor receptors (TNFR) on tumor endothelial cells (TEC). The goals of the present work were: 1) to identify differences in expression of genes encoding the scaffolding proteins and glycosyl transferases associated with PNAd biosynthesis in TEC and lymph node blood endothelial cells (LN BEC); and 2) to determine which of these PNAd associated components are regulated by TNFR signaling. We found that the same genes encoding scaffolding proteins and glycosyl transferases were upregulated in PNAd+ LN BEC and PNAd+ TEC relative to their PNAdneg counterparts. The lower level of PNAd expression on TEC vs LN BEC was associated with relatively lower expression of these genes, particularly the carbohydrate sulfotransferase Chst4. Loss of PNAd on TEC in the absence of TNFR signaling was associated with lack of upregulation of these same genes. A small subset of PNAd+ TEC remaining in the absence of TNFR signaling showed normal upregulation of a subset of these genes, but reduced upregulation of genes encoding the scaffolding proteins podocalyxin and nepmucin, and carbohydrate sulfotransferase Chst2. Lastly, we found that checkpoint immunotherapy augmented both the fraction of TEC expressing PNAd and their surface level of this ligand. This work points to strong similarities in the regulation of PNAd expression on TEC by TNFR signaling and on LN BEC by lymphotoxin-β receptor signaling, and provides a platform for the development of novel strategies that manipulate PNAd expression on tumor vasculature as an element of cancer immunotherapy.
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Affiliation(s)
| | | | - Victor H. Engelhard
- Carter Immunology Center and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, United States
- *Correspondence: Victor H. Engelhard,
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30
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Hussain B, Kasinath V, Ashton-Rickardt GP, Clancy T, Uchimura K, Tsokos G, Abdi R. High endothelial venules as potential gateways for therapeutics. Trends Immunol 2022; 43:728-740. [PMID: 35931612 PMCID: PMC10804419 DOI: 10.1016/j.it.2022.07.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/05/2022] [Accepted: 07/08/2022] [Indexed: 01/22/2023]
Abstract
High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases.
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Affiliation(s)
- Bilal Hussain
- Transplantation Research Center and Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Vivek Kasinath
- Transplantation Research Center and Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | | | - Thomas Clancy
- Division of Surgical Oncology, Brigham and Women's Hospital, Boston, MA, USA
| | - Kenji Uchimura
- University Lille, CNRS, UMR8576 - UGSF - Unite de Glycogiologie Structurale et Functionelle, 59000 Lille, France
| | - George Tsokos
- Division of Rheumatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Reza Abdi
- Transplantation Research Center and Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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31
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Hashemi G, Dight J, Khosrotehrani K, Sormani L. Melanoma Tumour Vascularization and Tissue-Resident Endothelial Progenitor Cells. Cancers (Basel) 2022; 14:4216. [PMID: 36077754 PMCID: PMC9454996 DOI: 10.3390/cancers14174216] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/20/2022] Open
Abstract
The aggressiveness of solid cancers, such as melanoma, relies on their metastatic potential. It has become evident that this key cause of mortality is largely conferred by the tumour-associated stromal cells, especially endothelial cells. In addition to their essential role in the formation of the tumour vasculature, endothelial cells significantly contribute to the establishment of the tumour microenvironment, thus enabling the dissemination of cancer cells. Melanoma tumour vascularization occurs through diverse biological processes. Vasculogenesis is the formation of de novo blood vessels from endothelial progenitor cells (EPCs), and recent research has shown the role of EPCs in melanoma tumour vascularization. A more detailed understanding of the complex role of EPCs and how they contribute to the abnormal vessel structures in tumours is of importance. Moreover, anti-angiogenic drugs have a limited effect on melanoma tumour vascularization, and the role of these drugs on EPCs remains to be clarified. Overall, targeting cancer vasculature remains a challenge, and the role of anti-angiogenic drugs and combination therapies in melanoma, a focus of this review, is an area of extensive exploration.
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Affiliation(s)
| | | | - Kiarash Khosrotehrani
- Experimental Dermatology Group, Dermatology Research Centre, The UQ Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
| | - Laura Sormani
- Experimental Dermatology Group, Dermatology Research Centre, The UQ Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
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32
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Blanchard L, Girard JP. [Tumor-associated HEVs mediate lymphocyte entry into tumors during cancer immunotherapy]. Med Sci (Paris) 2022; 38:631-634. [PMID: 36094227 DOI: 10.1051/medsci/2022090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Lucas Blanchard
- Institut de pharmacologie et de biologie structurale, IPBS, université de Toulouse, CNRS, UPS, Toulouse, France
| | - Jean-Philippe Girard
- Institut de pharmacologie et de biologie structurale, IPBS, université de Toulouse, CNRS, UPS, Toulouse, France
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Vaghjiani RG, Skitzki JJ. Tertiary Lymphoid Structures as Mediators of Immunotherapy Response. Cancers (Basel) 2022; 14:cancers14153748. [PMID: 35954412 PMCID: PMC9367241 DOI: 10.3390/cancers14153748] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Tertiary lymphoid structures (TLS) are anatomic entities that are similar to, but distinct from, secondary lymphoid structures (e.g., lymph nodes) that allow for a host’s own immune system to respond in a more targeted and efficacious way. TLS are increasingly recognized as markers of prognosis in cancer patients and are now being implicated as direct mediators of immunotherapy efficacy. The inherent properties of TLS, as well as their cellular constituents, are being elucidated across tumor types, with commonalities becoming more apparent. Given the importance of TLS in a patient’s response to malignancy, the ability to induce TLS promises to be an advantageous therapeutic avenue and already appears feasible in preclinical models. Abstract Since its first application in the treatment of cancer during the 1800s, immunotherapy has more recently become the leading edge of novel treatment strategies. Even though the efficacy of these agents can at times be predicted by more traditional metrics and biomarkers, often patient responses are variable. TLS are distinct immunologic structures that have been identified on pathologic review of various malignancies and are emerging as important determinants of patient outcome. Their presence, location, composition, and maturity are critically important in a host’s response to malignancy. Because of their unique immunogenic niche, they are also prime candidates, not only to predict and measure the efficacy of immunotherapy agents, but also to be potentially inducible gatekeepers to increase therapeutic efficacy. Herein, we review the mechanistic underpinnings of TLS formation, the data on its relationship to various malignancies, and the emerging evidence for the role of TLS in immunotherapy function.
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Affiliation(s)
- Raj G. Vaghjiani
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Joseph J. Skitzki
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Correspondence:
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Rossi A, Belmonte B, Carnevale S, Liotti A, De Rosa V, Jaillon S, Piconese S, Tripodo C. Stromal and Immune Cell Dynamics in Tumor Associated Tertiary Lymphoid Structures and Anti-Tumor Immune Responses. Front Cell Dev Biol 2022; 10:933113. [PMID: 35874810 PMCID: PMC9304551 DOI: 10.3389/fcell.2022.933113] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Tertiary lymphoid structures (TLS) are ectopic lymphoid organs that have been observed in chronic inflammatory conditions including cancer, where they are thought to exert a positive effect on prognosis. Both immune and non-immune cells participate in the genesis of TLS by establishing complex cross-talks requiring both soluble factors and cell-to-cell contact. Several immune cell types, including T follicular helper cells (Tfh), regulatory T cells (Tregs), and myeloid cells, may accumulate in TLS, possibly promoting or inhibiting their development. In this manuscript, we propose to review the available evidence regarding specific aspects of the TLS formation in solid cancers, including 1) the role of stromal cell composition and architecture in the recruitment of specific immune subpopulations and the formation of immune cell aggregates; 2) the contribution of the myeloid compartment (macrophages and neutrophils) to the development of antibody responses and the TLS formation; 3) the immunological and metabolic mechanisms dictating recruitment, expansion and plasticity of Tregs into T follicular regulatory cells, which are potentially sensitive to immunotherapeutic strategies directed to costimulatory receptors or checkpoint molecules.
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Affiliation(s)
- Alessandra Rossi
- Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Beatrice Belmonte
- Tumor Immunology Unit, Department of Sciences for Health Promotion and Mother-Child Care “G. D’Alessandro”, University of Palermo, Palermo, Italy
| | | | - Antonietta Liotti
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche, Naples, Italy
| | - Veronica De Rosa
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche, Naples, Italy
| | - Sebastien Jaillon
- RCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvia Piconese
- Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- IRCCS Fondazione Santa Lucia, Unità di Neuroimmunologia, Rome, Italy
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Rome, Italy
- *Correspondence: Silvia Piconese,
| | - Claudio Tripodo
- Tumor Immunology Unit, Department of Sciences for Health Promotion and Mother-Child Care “G. D’Alessandro”, University of Palermo, Palermo, Italy
- Histopathology Unit, FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
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35
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Lauss M, Donia M, Svane IM, Jönsson G. B Cells and Tertiary Lymphoid Structures: Friends or Foes in Cancer Immunotherapy? Clin Cancer Res 2022; 28:1751-1758. [PMID: 34965949 PMCID: PMC9306440 DOI: 10.1158/1078-0432.ccr-21-1130] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/26/2021] [Accepted: 12/20/2021] [Indexed: 01/07/2023]
Abstract
Tumor cells pose a challenge to the adaptive immune system, and its key cell types, T and B cells, have frequently been associated with an improved prognosis. The success of immune checkpoint blockade has confirmed the relevance of T cells. However, the role of B cells is increasingly recognized, and highlighted in this review. Recent data suggest that tumors contain a diverse set of B cells reflecting different developmental states and exerting functions such as antigen presentation, antibody production, and regulatory effects. Further, B cells are frequently located in tertiary lymphoid structures (TLS), which are immune cell niches that sustain an immune response at sites of chronic inflammation. TLSs in tumors display substantial heterogeneity, ranging from cell aggregates to mature structures with an active germinal center. Recent studies have provided insights into initiation, cellular and spatial composition, and function of TLS in a variety of cancer types; however, several critical issues still need to be resolved. Currently, initial reports are discerning the role of TLSs in immunotherapy, with the majority of studies observing TLSs to confer favorable patient outcome. Finally, TLS induction in tumors is evaluated, with the therapeutic aim to reactivate the host immune response.
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Affiliation(s)
- Martin Lauss
- Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden
- Lund University Cancer Center, Lund, Sweden
| | - Marco Donia
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Göran Jönsson
- Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden
- Lund University Cancer Center, Lund, Sweden
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36
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Peripheral node addressin, a ligand for L-selectin is found in tumor cells and in high endothelial venules in endometrial cancer. Pathol Res Pract 2022; 233:153888. [DOI: 10.1016/j.prp.2022.153888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 11/18/2022]
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37
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Rodgers CB, Mustard CJ, McLean RT, Hutchison S, Pritchard AL. A B-cell or a key player? The different roles of B-cells and antibodies in melanoma. Pigment Cell Melanoma Res 2022; 35:303-319. [PMID: 35218154 PMCID: PMC9314792 DOI: 10.1111/pcmr.13031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 02/01/2022] [Accepted: 02/21/2022] [Indexed: 12/17/2022]
Abstract
The B‐cell system plays an important role in the melanoma immune response; however, consensus has yet to be reached in many facets. Here, we comprehensively review human studies only, due to fundamental differences in the humoral response with animal models. Tumour‐infiltrating B‐cells are associated with contradictory prognostic values, reflecting a lack of agreement between studies on cell subset classification and differences in the markers used, particularly the common use of a single marker not differentiating multiple subsets. Tertiary lymphoid structures (TLS) organise T‐cells and B‐cells within tumours to generate a local anti‐tumour response and TLS presence associates with improved survival in response to immune checkpoint blockade, in late‐stage disease. Autoantibody production is increased in melanoma patients and has been proposed as biomarkers for diagnosis, prognosis and treatment/toxicity response; however, no consistent targets are yet identified. The function of antibodies in an anti‐tumour response is determined by its isotype and subclass; IgG4 is immune‐suppressive and robustly correlate with poor patient survival in melanoma. We conclude that the current B‐cell literature needs careful interpretation based on the methods used and that we need a consensus of markers to define B‐cells and associated lymphoid organs. Furthermore, future studies need to not only examine antibody targets, but also isotypes when considering functional roles.
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Affiliation(s)
- Chloe B Rodgers
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Colette J Mustard
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Ryan T McLean
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Sharon Hutchison
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Antonia L Pritchard
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
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38
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Kang J, li N, Wang F, Wei Y, Zeng Y, Luo Q, Sun X, Xu H, Peng J, Zhou F. Exploration of Reduced Mitochondrial Content–Associated Gene Signature and Immunocyte Infiltration in Colon Adenocarcinoma by an Integrated Bioinformatic Analysis. Front Genet 2022; 13:832331. [PMID: 35464857 PMCID: PMC9024084 DOI: 10.3389/fgene.2022.832331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/14/2022] [Indexed: 12/11/2022] Open
Abstract
Purpose: Mitochondrial dysfunction refers to cancer immune evasion. A novel 7-gene prognostic signature related to the mitochondrial DNA copy number was utilized to evaluate the immunocyte infiltration in colon cancer according to the risk scores and to predict the survival for colon cancer.Experimental design: We performed an integrated bioinformatic analysis to analyze transcriptome profiling of the EB-treated mitochondrial DNA–defected NCM460 cell line with differentially expressed genes between tumor and normal tissues of COAD in TCGA. The LASSO analysis was utilized to establish a prognostic signature. ESTIMATE and CIBERSORT validated the differences of immunocyte infiltration between colon cancer patients with high- and low-risk scores.Results: Our study identified a 7-gene prognostic signature (LRRN2, ANKLE1, GPRASP1, PRAME, TCF7L1, RAB6B, and CALB2). Patients with colon cancer were split into the high- and low-risk group by the risk scores in TCGA (training cohort: HR = 2.50 p < 0.0001) and GSE39582 (validation cohort: HR = 1.43 p < 0.05). ESTIMATE and CIBERSORT revealed diverseness of immune infiltration in the two groups, especially downregulated T-cell infiltration in the patients with high-risk scores. Finally, we validated the colon patients with a low expression of the mitochondrial number biomarker TFAM had less CD3+ and CD8+ T-cell infiltration in clinical specimens.Conclusion: An mtDNA copy number-related 7-gene prognostic signature was investigated and evaluated, which may help to predict the prognosis of colon cancer patients and to guide clinical immunotherapy via immunocyte infiltration evaluation.
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Affiliation(s)
- Jinlin Kang
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Na li
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
- Renmin Hospital of Wuhan University, Wuhan, China
| | - Fen Wang
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Yan Wei
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Yangyang Zeng
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Qifan Luo
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Xuehua Sun
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Hui Xu
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
| | - Jin Peng
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
- *Correspondence: Jin Peng, ; Fuxiang Zhou,
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital Wuhan University, Wuhan, China
- Hubei Province Key Laboratory of Tumor Biological Behaviors, Wuhan, China
- Hubei Cancer Clinical Study Center, Wuhan, China
- *Correspondence: Jin Peng, ; Fuxiang Zhou,
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39
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Sawada J, Hiraoka N, Qi R, Jiang L, Fournier-Goss AE, Yoshida M, Kawashima H, Komatsu M. Molecular Signature of Tumor-Associated High Endothelial Venules That Can Predict Breast Cancer Survival. Cancer Immunol Res 2022; 10:468-481. [PMID: 35201289 DOI: 10.1158/2326-6066.cir-21-0369] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 10/11/2021] [Accepted: 02/18/2022] [Indexed: 11/16/2022]
Abstract
High endothelial venules (HEV) are specialized post-capillary venules that recruit naïve lymphocytes to lymph nodes. HEVs are essential for the development of adaptive immunity. HEVs can also develop in tumors where they are thought to be important for recruiting naïve T cells and B cells into the tumors and locally enhancing antitumor immunity by supporting the formation of tertiary lymphoid structures. Herein, we used comparative transcriptome analysis of human breast cancer to investigate genes differentially expressed between tumor-associated HEVs and the rest of the tumor vasculature. Tumor vessels highly expressing HEV-upregulated genes, such as the homeobox gene MEOX2 and the tetraspanin gene TSPAN7, were associated with extensive infiltration of T and B cells and the occurrence of tertiary lymphoid structures, which is known to predict therapeutic responses to immune-checkpoint inhibitors. Moreover, high transcript counts of these genes in clinical tumor specimens were associated with a significant survival benefit in advanced breast cancer. The molecular signature of HEVs identified herein may be useful for guiding immunotherapies and provides a new direction for investigating tumor-associated HEVs and their clinical significance. See related Spotlight by Gallimore, p. 371.
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Affiliation(s)
- Junko Sawada
- Cancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, Florida.,Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital/Division of Molecular Pathology, Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Rongsu Qi
- Department of Health Informatics, Johns Hopkins All Children's Hospital, St. Petersburg, Florida
| | - Lu Jiang
- Cancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, Florida.,Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ashley E Fournier-Goss
- Cancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, Florida.,Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Masayuki Yoshida
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital/Division of Molecular Pathology, Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroto Kawashima
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Masanobu Komatsu
- Cancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, Florida.,Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
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40
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Jin Z, Kang J, Yu T. Feature selection and classification over the network with missing node observations. Stat Med 2022; 41:1242-1262. [PMID: 34816464 PMCID: PMC9773124 DOI: 10.1002/sim.9267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/14/2021] [Accepted: 10/29/2021] [Indexed: 12/25/2022]
Abstract
Jointly analyzing transcriptomic data and the existing biological networks can yield more robust and informative feature selection results, as well as better understanding of the biological mechanisms. Selecting and classifying node features over genome-scale networks has become increasingly important in genomic biology and genomic medicine. Existing methods have some critical drawbacks. The first is they do not allow flexible modeling of different subtypes of selected nodes. The second is they ignore nodes with missing values, very likely to increase bias in estimation. To address these limitations, we propose a general modeling framework for Bayesian node classification (BNC) with missing values. A new prior model is developed for the class indicators incorporating the network structure. For posterior computation, we resort to the Swendsen-Wang algorithm for efficiently updating class indicators. BNC can naturally handle missing values in the Bayesian modeling framework, which improves the node classification accuracy and reduces the bias in estimating gene effects. We demonstrate the advantages of our methods via extensive simulation studies and the analysis of the cutaneous melanoma dataset from The Cancer Genome Atlas.
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Affiliation(s)
| | - Jian Kang
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Tianwei Yu
- School of Data Science and Warshel Institute, The Chinese University of Hong Kong - Shenzhen, and Shenzhen Research Institute of Big Data, Shenzhen, China
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41
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Asrir A, Tardiveau C, Coudert J, Laffont R, Blanchard L, Bellard E, Veerman K, Bettini S, Lafouresse F, Vina E, Tarroux D, Roy S, Girault I, Molinaro I, Martins F, Scoazec JY, Ortega N, Robert C, Girard JP. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell 2022; 40:318-334.e9. [PMID: 35120598 DOI: 10.1016/j.ccell.2022.01.002] [Citation(s) in RCA: 139] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/23/2021] [Accepted: 01/07/2022] [Indexed: 02/07/2023]
Abstract
Recruitment of lymphocytes into tumors is critical for anti-tumor immunity and efficacious immunotherapy. We show in murine models that tumor-associated high endothelial venules (TA-HEVs) are major sites of lymphocyte entry into tumors at baseline and upon treatment with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB). TA-HEV endothelial cells (TA-HECs) derive from post-capillary venules, co-express MECA-79+ HEV sialomucins and E/P-selectins, and are associated with homing and infiltration into tumors of various T cell subsets. Intravital microscopy further shows that TA-HEVs are the main sites of lymphocyte arrest and extravasation into ICB-treated tumors. Increasing TA-HEC frequency and maturation increases the proportion of tumor-infiltrating stem-like CD8+ T cells, and ameliorates ICB efficacy. Analysis of tumor biopsies from 93 patients with metastatic melanoma reveals that TA-HEVs are predictive of better response and survival upon treatment with anti-PD-1/anti-CTLA-4 combination. These studies provide critical insights into the mechanisms governing lymphocyte trafficking in cancer immunity and immunotherapy.
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Affiliation(s)
- Assia Asrir
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Claire Tardiveau
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Juliette Coudert
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Robin Laffont
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Lucas Blanchard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Elisabeth Bellard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Krystle Veerman
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Sarah Bettini
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Fanny Lafouresse
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Estefania Vina
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Dorian Tarroux
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Severine Roy
- Department of Medicine, Gustave Roussy, Villejuif, France; INSERM U981, Gustave Roussy, Villejuif, France
| | - Isabelle Girault
- Department of Medicine, Gustave Roussy, Villejuif, France; INSERM U981, Gustave Roussy, Villejuif, France
| | - Irma Molinaro
- Department of Pathology, Gustave Roussy, Villejuif, France
| | - Frédéric Martins
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, UMR1048, INSERM, UPS, Toulouse, France; Plateforme Genome et Transcriptome, GeT, Genopole Toulouse, France
| | - Jean-Yves Scoazec
- INSERM U981, Gustave Roussy, Villejuif, France; Department of Pathology, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France; AMMICa, CNRS-UAR 3655 and INSERM-US23, Gustave Roussy, Villejuif, France
| | - Nathalie Ortega
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Caroline Robert
- Department of Medicine, Gustave Roussy, Villejuif, France; INSERM U981, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
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42
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Gowhari Shabgah A, Al-Obaidi ZMJ, Sulaiman Rahman H, Kamal Abdelbasset W, Suksatan W, Bokov DO, Thangavelu L, Turki Jalil A, Jadidi-Niaragh F, Mohammadi H, Mashayekhi K, Gholizadeh Navashenaq J. Does CCL19 act as a double-edged sword in cancer development? Clin Exp Immunol 2021; 207:164-175. [PMID: 35020885 PMCID: PMC8982982 DOI: 10.1093/cei/uxab039] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 11/08/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is considered a life-threatening disease, and several factors are involved in its development. Chemokines are small proteins that physiologically exert pivotal roles in lymphoid and non-lymphoid tissues. The imbalance or dysregulation of chemokines has contributed to the development of several diseases, especially cancer. CCL19 is one of the homeostatic chemokines that is abundantly expressed in the thymus and lymph nodes. This chemokine, which primarily regulates immune cell trafficking, is involved in cancer development. Through the induction of anti-tumor immune responses and inhibition of angiogenesis, CCL19 exerts tumor-suppressive functions. In contrast, CCL19 also acts as a tumor-supportive factor by inducing inflammation, cell growth, and metastasis. Moreover, CCL19 dysregulation in several cancers, including colorectal, breast, pancreatic, and lung cancers, has been considered a tumor biomarker for diagnosis and prognosis. Using CCL19-based therapeutic approaches has also been proposed to overcome cancer development. This review will shed more light on the multifarious function of CCL19 in cancer and elucidate its application in diagnosis, prognosis, and even therapy. It is expected that the study of CCL19 in cancer might be promising to broaden our knowledge of cancer development and might introduce novel approaches in cancer management.
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Affiliation(s)
| | - Zaid Mahdi Jaber Al-Obaidi
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Alkafeel, Najaf, Iraq,Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Karbala, Iraq
| | - Heshu Sulaiman Rahman
- Department of Physiology, College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq,Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimaniyah, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia,Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Dmitry O Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation,Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russian Federation
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha institute of medical and Technical Sciences, Saveetha University, Chennai, India
| | - Abduladheem Turki Jalil
- Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, Grodno, Belarus,College of Technical Engineering, The Islamic University, Najaf, Iraq
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran,Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Kazem Mashayekhi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran,Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Jamshid Gholizadeh Navashenaq
- Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran,Correspondence: Jamshid Gholizadeh Navashenaq, Bam University of Medical Sciences, Bam, Kerman, Iran. E-mail: ;
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43
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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44
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Jones D, Wang Z, Chen IX, Zhang S, Banerji R, Lei PJ, Zhou H, Xiao V, Kwong C, van Wijnbergen JWM, Pereira ER, Vakoc BJ, Huang P, Nia HT, Padera TP. Solid stress impairs lymphocyte infiltration into lymph-node metastases. Nat Biomed Eng 2021; 5:1426-1436. [PMID: 34282290 PMCID: PMC8678215 DOI: 10.1038/s41551-021-00766-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 06/17/2021] [Indexed: 02/06/2023]
Abstract
Strong and durable anticancer immune responses are associated with the generation of activated cancer-specific T cells in the draining lymph nodes. However, cancer cells can colonize lymph nodes and drive tumour progression. Here, we show that lymphocytes fail to penetrate metastatic lesions in lymph nodes. In tissue from patients with breast, colon, and head and neck cancers, as well as in mice with spontaneously developing breast-cancer lymph-node metastases, we found that lymphocyte exclusion from nodal lesions is associated with the presence of solid stress caused by lesion growth, that solid stress induces reductions in the number of functional high endothelial venules in the nodes, and that relieving solid stress in the mice increased the presence of lymphocytes in lymph-node lesions by about 15-fold. Solid-stress-mediated impairment of lymphocyte infiltration into lymph-node metastases suggests a therapeutic route for overcoming T-cell exclusion during immunotherapy.
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Affiliation(s)
- Dennis Jones
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
| | - Zixiong Wang
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Ivy X Chen
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Sue Zhang
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Rohin Banerji
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Pin-Ji Lei
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Hengbo Zhou
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Victoria Xiao
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Cecilia Kwong
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Jan Willem M van Wijnbergen
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Ethel R Pereira
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Benjamin J Vakoc
- Harvard Medical School, Boston, MA, USA
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
| | - Peigen Huang
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Hadi T Nia
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Timothy P Padera
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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45
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Newnes HV, Armitage JD, Audsley KM, Bosco A, Waithman J. Directing the Future Breakthroughs in Immunotherapy: The Importance of a Holistic Approach to the Tumour Microenvironment. Cancers (Basel) 2021; 13:cancers13235911. [PMID: 34885021 PMCID: PMC8656826 DOI: 10.3390/cancers13235911] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Immunotherapies have changed the way we treat cancer and, while some patients have benefitted greatly, there are still those that do not respond to therapy. Understanding why some patients respond to therapy and others do not is critical in developing new immunotherapeutic strategies. The increasing awareness of the importance of investigating the tumour in its entirety, including the surrounding tissue and role of various immune cells is helping to differentiate responders and non-responders. In addition, the resolution gained by the development of sophisticated bioinformatic technologies allows for a deeper understanding of the complex roles of individual cells in the tumour. This advancement will be critical for the development of novel therapies to treat cancer. Abstract Immunotherapy has revolutionised the treatment of cancers by exploiting the immune system to eliminate tumour cells. Despite the impressive response in a proportion of patients, clinical benefit has been limited thus far. A significant focus to date has been the identification of specific markers associated with response to immunotherapy. Unfortunately, the heterogeneity between patients and cancer types means identifying markers of response to therapy is inherently complex. There is a growing appreciation for the role of the tumour microenvironment (TME) in directing response to immunotherapy. The TME is highly heterogeneous and contains immune, stromal, vascular and tumour cells that all communicate and interact with one another to form solid tumours. This review analyses major cell populations present within the TME with a focus on their diverse and often contradictory roles in cancer and how this informs our understanding of immunotherapy. Furthermore, we discuss the role of integrated omics in providing a comprehensive view of the TME and demonstrate the potential of leveraging multi-omics to decipher the underlying mechanisms of anti-tumour immunity for the development of novel immunotherapeutic strategies.
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Qin M, Jin Y, Pan LY. Tertiary lymphoid structure and B-cell-related pathways: A potential target in tumor immunotherapy. Oncol Lett 2021; 22:836. [PMID: 34712360 PMCID: PMC8548801 DOI: 10.3892/ol.2021.13097] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/28/2021] [Indexed: 01/11/2023] Open
Abstract
The tertiary lymphoid structure (TLS), also referred to as the ectopic lymphoid structure, has recently become a focus of attention. The TLS consists of T-cell and B-cell-rich regions, as well as plasma cells, follicular helper T cells, follicular dendritic cells (FDCs), germinal centers (GCs) and high endothelial venules. TLSs can be divided into different subtypes and mature stages according to the density of FDCs and GCs. The TLS serves as an effective site in which an antitumor inflammatory response is generated through infiltrating immune cells. B-cell-related pathways, known as the CXC chemokine ligand 13/CXC chemokine receptor type 5 axis and the CC chemokine ligand (CCL)19/CCL21/CC-chemokine receptor 7 axis, play a key role in the generation and formation of TLSs. The aim of the present review was to systematically summarize updated research progress on the formation, subtypes, evaluation and B-cell-related pathways of TLSs. Furthermore, researchers have previously reported that TLSs are present in several types of solid cancers and that they are associated with survival outcomes. Therefore, studies on TLS in breast, lung, colorectal and ovarian cancers and melanoma were summarized and compared. The TLS and B-cell-related pathways require further investigation as important immune signals and promising new immunotherapy targets in the era of T-cell therapy revolution.
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Affiliation(s)
- Meng Qin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.,Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing 100730, P.R. China
| | - Ying Jin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.,Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing 100730, P.R. China
| | - Ling-Ya Pan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.,Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing 100730, P.R. China
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Park HS, Kim YM, Kim S, Lee WS, Kong SJ, Yang H, Kang B, Cheon J, Shin SJ, Kim C, Chon HJ. High endothelial venule is a surrogate biomarker for T-cell inflamed tumor microenvironment and prognosis in gastric cancer. J Immunother Cancer 2021; 9:jitc-2021-003353. [PMID: 34670828 PMCID: PMC8529985 DOI: 10.1136/jitc-2021-003353] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2021] [Indexed: 12/20/2022] Open
Abstract
Background High endothelial venule (HEV) is a specialized vasculature for lymphocyte trafficking. While HEVs are frequently observed within gastric cancer (GC), the vascular–immune interaction between HEV and tumor-infiltrating lymphocytes (TILs) has not been well elucidated. In this study, we aimed to unveil the potential value of HEVs as a surrogate marker for T-cell inflamed immune microenvironment in GC using a large number of prospectively collected surgical specimens of GC. Methods We included 460 patients with GC who underwent surgical resection. Nanostring PanCancer immune profiling was performed to evaluate the immunological phenotype of GCs. HEV density and three distinct patterns of TILs (Crohn-like lymphoid reaction, peritumoral lymphoid reaction, and intratumoral lymphoid reaction) were analyzed for their relationship and evaluated as prognostic factors for relapse-free survival (RFS) and overall survival (OS). Results HEV-high GC revealed increased infiltration by immune cell subsets, including dendritic cells, CD8+ cytotoxic T cells, and CD4+ helper T cells. In addition, HEV-high GC demonstrated increased immune-modulating chemokines, type I or II interferon pathway, and immune checkpoints, all of which indicate the inflamed tumor microenvironment (TME). All three distinct patterns of TILs were associated with HEV density. In survival analysis, patients with HEV-high GC displayed significantly longer RFS and OS than those with HEV-low GC (p<0.001 for RFS, p<0.001 for OS). Multivariate analysis demonstrated that HEV was the most significant immunological prognostic factor for RFS (patients with high HEV compared with those with low HEV; HR 0.412, 95% CI 0.241 to 0.705, p=0.001) and OS (HR 0.547, 95% CI 0.329 to 0.909, p=0.02) after adjustment for age, stage, and TIL. Conclusion HEV is the most significant immunological prognosticator for RFS and OS in resected GC, indicating inflamed TME.
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Affiliation(s)
- Hyung Soon Park
- Division of Medical Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)
| | - Yoo Min Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Sewha Kim
- Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Won Suk Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - So Jung Kong
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Hannah Yang
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Beodeul Kang
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Jaekyung Cheon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Su-Jin Shin
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Chan Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
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Mustapha R, Ng K, Monypenny J, Ng T. Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis. Front Mol Biosci 2021; 8:661516. [PMID: 34568423 PMCID: PMC8455920 DOI: 10.3389/fmolb.2021.661516] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics.
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Affiliation(s)
- Rami Mustapha
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, United Kingdom
- Cancer Research UK King’s Health Partners Centre, London, United Kingdom
| | - Kenrick Ng
- UCL Cancer Institute, University College London, London, United Kingdom
- Department of Medical Oncology, University College Hospitals NHS Foundation Trust, London, United Kingdom
| | - James Monypenny
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, United Kingdom
| | - Tony Ng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, United Kingdom
- Cancer Research UK King’s Health Partners Centre, London, United Kingdom
- UCL Cancer Institute, University College London, London, United Kingdom
- Cancer Research UK City of London Centre, London, United Kingdom
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Vella G, Guelfi S, Bergers G. High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer. Front Immunol 2021; 12:736670. [PMID: 34484246 PMCID: PMC8416033 DOI: 10.3389/fimmu.2021.736670] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 07/30/2021] [Indexed: 01/22/2023] Open
Abstract
High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3+T cell-enriched areas with fewer CD20+B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies. Here, we discuss the current insight into TU-HEV formation, function, and regulation in tumors and elaborate on the functional implication, opportunities, and challenges of TU-HEV formation for cancer immunotherapy.
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Affiliation(s)
- Gerlanda Vella
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, Vlaams Instituut voor Biotechnologie (VIB)-Center for Cancer Biology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Sophie Guelfi
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, Vlaams Instituut voor Biotechnologie (VIB)-Center for Cancer Biology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Gabriele Bergers
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, Vlaams Instituut voor Biotechnologie (VIB)-Center for Cancer Biology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Neurological Surgery, UCSF Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, CA, United States
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Recent Advances in Glioma Therapy: Combining Vascular Normalization and Immune Checkpoint Blockade. Cancers (Basel) 2021; 13:cancers13153686. [PMID: 34359588 PMCID: PMC8345045 DOI: 10.3390/cancers13153686] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/09/2021] [Accepted: 07/19/2021] [Indexed: 12/28/2022] Open
Abstract
Glioblastoma (GBM) accounts for more than 50% of all primary malignancies of the brain. Current standard treatment regimen for GBM includes maximal surgical resection followed by radiation and adjuvant chemotherapy. However, due to the heterogeneity of the tumor cells, tumor recurrence is often inevitable. The prognosis of patients with glioma is, thus, dismal. Glioma is a highly angiogenic tumor yet immunologically cold. As such, evolving studies have focused on designing strategies that specifically target the tyrosine kinase receptors of angiokines and encourage immune infiltration. Recent promising results from immunotherapies on other cancer types have prompted further investigations of this therapy in GBM. In this article, we reviewed the pathological angiogenesis and immune reactivity in glioma, as well as its target for drug development, and we discussed future directions in glioma therapy.
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