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Ji C, Kumpf S, Qian J, Federspiel JD, Sheehan M, Capunitan D, Atallah E, Astbury S, Arat S, Oziolor E, Ocana MF, Ramaiah SK, Grove J, Aithal GP, Lanz TA. Transcriptomic and proteomic characterization of cell and protein biomarkers of checkpoint inhibitor-induced liver injury. Cancer Immunol Immunother 2025; 74:190. [PMID: 40317333 PMCID: PMC12049347 DOI: 10.1007/s00262-025-04033-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 03/24/2025] [Indexed: 05/07/2025]
Abstract
Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy, but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were sequenced for by transcriptomic and T cell receptor repertoire (bulk and single-cell immune profiling), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and proteins in peripheral blood mononuclear cells (PBMCs) and plasma in response to liver injury. Onset of ChILI was accompanied by an increase in T cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8 + effector memory cells), while CD16 + monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with ChILI onset. These findings provide valuable insights into the immune and molecular mechanisms underlying ChILI as well as potential biomarkers of ChILI.Trial registration number NCT04476563.
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Affiliation(s)
- Changhua Ji
- Drug Safety R&D, Pfizer Inc, 10777 Science Center Dr., La Jolla, CA, 92121, USA.
| | - Steven Kumpf
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA
| | - Jessie Qian
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA
| | | | - Mark Sheehan
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA
| | - Darien Capunitan
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA
| | - Edmond Atallah
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Stuart Astbury
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Seda Arat
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA
| | - Elias Oziolor
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA
| | | | | | - Jane Grove
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Thomas A Lanz
- Drug Safety R&D, Pfizer Inc, Eastern Point Rd, 274-3715A, Groton, CT, 06340, USA.
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Adams S, Demaria S, Rinchai D, Wang E, Novik Y, Oratz R, Fenton-Kerimian M, Levine PG, Li X, Marincola F, Jin P, Stroncek D, Goldberg J, Bedognetti D, Formenti SC. Topical TLR7 agonist and radiotherapy in patients with metastatic breast cancer. J Immunother Cancer 2025; 13:e011173. [PMID: 40187749 PMCID: PMC11973781 DOI: 10.1136/jitc-2024-011173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/19/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Toll-like receptor (TLR) agonists and radiation therapy hold promise for cancer immunotherapy. We conducted a phase I/II trial combining topical imiquimod (IMQ, a TLR-7 agonist) and local radiotherapy (RT) in patients with metastatic breast cancer accompanied by longitudinal transcriptional analysis of tumor biopsies. METHODS The primary objective of the trial (NCT01421017) was to assess systemic responses by immune-related response criteria (irRC) after an 8-week cycle of topical IMQ and concurrent local RT (cohort 1). An amendment to the trial added two cohorts, both received one dose of cyclophosphamide (CTX) administered 1 week before study treatment initiation, IMQ/RT/CTX (cohort 2) and RT/CTX control (cohort 3). Cutaneous metastases were prospectively assigned to treatment with IMQ and RT (area A) or IMQ alone (area B). Secondary objectives were safety (Common Terminology Criteria for Adverse Events criteria) and local response in skin metastases. In all IMQ cohorts, tumors were biopsied before treatment and at 2 and 3 weeks. RESULTS 31 patients were enrolled (n=12, n=12, and n=7, in cohort 1, 2, and 3, respectively), with 4 out of 24 patients in the IMQ cohorts showing systemic tumor responses (two complete responses (CR) and two partial responses (PR)). No objective responses were observed in the seven patients enrolled in the control arm (RT alone). The treatment was well-tolerated, no grade 4-5 treatment-related adverse events occurred and grade 3 AEs were manageable (anemia, local pain, and local ulceration, n=1 each). Local objective responses were observed in 19/24 (9 CR and 10 PR) and 5/24 (5 PR) in areas treated with combined IMQ-RT and IMQ alone, respectively (p<0.001). All 24 patients treated with IMQ underwent serial biopsies, and 84 samples yielded sufficient material for transcriptional analyses. These revealed that the presence of a T-helper 1 functional orientation of the tumor microenvironment paralleled by the downregulation of DNA-repair genes was associated with CR after IMQ+RT, but not after IMQ alone. No post-treatment activation of immune-effector functions was observed in stable and progressing lesions. CONCLUSIONS Our findings support the safety and clinical efficacy of combining topical IMQ with local RT for recurrent breast cancer, with evidence of local and occasional systemic antitumor activity. TRIAL REGISTRATION NUMBER NCT01421017.
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Affiliation(s)
- Sylvia Adams
- Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medicine, New York, New York, USA
| | | | - Ena Wang
- Sidra Medical and Research Center, Ar-Rayyan, Qatar
| | - Yelena Novik
- Department of Medicine, NYU Langone Health, New York, New York, USA
| | - Ruth Oratz
- Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA
| | | | | | - Xiaochun Li
- Division of Biostatistics, NYU Langone Health, New York, New York, USA
| | | | - Ping Jin
- National Institutes of Health, Bethesda, Maryland, USA
| | | | - Judith Goldberg
- Population Health, NYU Grossman School of Medicine, New York, New York, USA
- NYU Grossman School of Medicine
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Sherif S, Roelands J, Mifsud W, Ahmed EI, Raynaud CM, Rinchai D, Sathappan A, Maaz A, Saleh A, Ozer E, Fakhro KA, Mifsud B, Thorsson V, Bedognetti D, Hendrickx WRL. The immune landscape of solid pediatric tumors. J Exp Clin Cancer Res 2022; 41:199. [PMID: 35690832 PMCID: PMC9188257 DOI: 10.1186/s13046-022-02397-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 05/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart.
Methods
We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome.
Results
A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS.
Conclusions
We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
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Hont AB, Dumont B, Sutton KS, Anderson J, Kentsis A, Drost J, Hong AL, Verschuur A. The tumor microenvironment and immune targeting therapy in pediatric renal tumors. Pediatr Blood Cancer 2022; 70 Suppl 2:e30110. [PMID: 36451260 DOI: 10.1002/pbc.30110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 12/04/2022]
Abstract
This review highlights the role of several immunomodulating elements contributing to the tumor microenvironment of various pediatric renal tumors including Wilms tumor. The roles of innate and adaptive immune cells in renal tumors are summarized as well as immunomodulatory cytokines and other proteins. The expression and the predictive role of checkpoint modulators like PD-L1 and immunomodulating proteins like glypican-3, B7-H3, COX-2 are highlighted with a translational view toward potential therapeutic innovations. We further discuss the current state of preclinical models in advancing this field of study. Finally, examples of clinical trials of immunomodulating strategies such as monoclonal antibodies and chimeric antigen receptor T (CAR-T) cells for relapsed/refractory/progressive pediatric renal tumors are described.
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Affiliation(s)
- Amy B Hont
- Department of Hematology/Oncology, Children's National Hospital, George Washington University, Washington, District of Columbia, USA
| | - Benoit Dumont
- Pediatric Hematology and Oncology Institute, Léon Bérard Cancer Center, Lyon, France
| | - Kathryn S Sutton
- Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
| | - John Anderson
- Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Alex Kentsis
- Tow Center for Developmental Oncology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York, USA
| | - Jarno Drost
- Princess Máxima Center and Oncode Institute, Utrecht, The Netherlands
| | - Andrew L Hong
- Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
| | - Arnauld Verschuur
- Department of Pediatric Hematology and Oncology, Hôpital d'Enfants de la Timone, APHM, Marseille, France
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Rinchai D, Verzoni E, Huber V, Cova A, Squarcina P, De Cecco L, de Braud F, Ratta R, Dugo M, Lalli L, Vallacchi V, Rodolfo M, Roelands J, Castelli C, Chaussabel D, Procopio G, Bedognetti D, Rivoltini L. Integrated transcriptional-phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients. Clin Transl Med 2021; 11:e434. [PMID: 34185403 PMCID: PMC8214860 DOI: 10.1002/ctm2.434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 05/09/2021] [Accepted: 05/12/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms. METHODS We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib. RESULTS Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells. CONCLUSIONS The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.
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Affiliation(s)
| | - Elena Verzoni
- Medical Oncology DepartmentFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Veronica Huber
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Agata Cova
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Paola Squarcina
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Loris De Cecco
- Platform of Integrated BiologyFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Filippo de Braud
- Medical Oncology DepartmentFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | | | - Matteo Dugo
- Platform of Integrated BiologyFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Luca Lalli
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Viviana Vallacchi
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Monica Rodolfo
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | | | - Chiara Castelli
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | | | - Giuseppe Procopio
- Medical Oncology DepartmentFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Davide Bedognetti
- Cancer Research DepartmentSidra MedicineDohaQatar
- Dipartimento di Medicina Interna e Specialità MedicheUniversità degli Studi di GenovaGenovaItaly
- College of Health and Life SciencesHamad Bin Khalifa UniversityDohaQatar
| | - Licia Rivoltini
- Unit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
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Abstract
A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness.
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Affiliation(s)
- Ena Wang
- Infectious Disease and Immunogenetics Section (IDIS); Department of Transfusion Medicine; Clinical Center and trans-NIH Center for Human Immunology (CHI); National Institutes of Health; Bethesda, MD USA
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Wang Y, Zhou Z, Chen L, Li Y, Zhou Z, Chu X. Identification of key genes and biological pathways in lung adenocarcinoma via bioinformatics analysis. Mol Cell Biochem 2021; 476:931-939. [PMID: 33130972 DOI: 10.1007/s11010-020-03959-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Lung adenocarcinoma (LUAD) accounts for the majority of cancer-related deaths worldwide. Our study identified key LUAD genes and their potential mechanism via bioinformatics analysis of public datasets. GSE10799, GSE40791, and GSE27262 microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database. The RobustRankAggreg package was used to perform a meta-analysis, and 50 upregulated genes and 87 downregulated genes overlapped in three datasets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Furthermore, protein-protein interaction (PPI) networks of the differentially expressed genes (DEGs) were built by the Search Tool for the Retrieval of Interacting Genes (STRING) and 22 core genes were identified by Molecular Complex Detection (MCODE) and visualized with Cytoscape. Subsequently, these core genes were analyzed by the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA). The results showed that all 22 genes were significantly associated with reduced survival rates. For GEPIA, the expression of only one gene was not significantly different between LUAD tissues and normal tissues. A KEGG pathway enrichment reanalysis of the 21 genes identified five key genes (CCNB1, BUB1B, CDC20, TTK, and MAD2L1) in the cell cycle pathway. Finally, the Comparative Toxicogenomics Database (CTD) website was used to explore the relationship between these key genes and certain drugs. Based on the bioinformatics analysis, five key genes were identified in LUAD, and drugs closely associated these genes can provide clues for the treatment and prognosis of LUAD.
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Affiliation(s)
- Yuanyuan Wang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Zihao Zhou
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Liang Chen
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Yuzheng Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Zengyuan Zhou
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Xia Chu
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China.
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Kovács A, Stenmark Tullberg A, Werner Rönnerman E, Holmberg E, Hartman L, Sjöström M, Lundstedt D, Malmström P, Fernö M, Karlsson P. Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of the SweBCG91RT Randomized Trial. J Clin Oncol 2019; 37:1179-1187. [DOI: 10.1200/jco.18.02157] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The effects of radiotherapy (RT) on the basis of the presence of stromal tumor infiltrating lymphocytes (TILs) have not been studied. The purpose of this study was to analyze the association of TILs with the effect of postoperative RT on ipsilateral breast tumor recurrence (IBTR) in a large randomized trial. METHODS In the SweBCT91RT (Swedish Breast Cancer Group 91 Radiotherapy) trial, 1,178 patients with breast cancer stage I and II were randomly assigned to breast-conserving surgery plus postoperative RT or breast-conserving surgery only and followed for a median of 15.2 years. Tumor blocks were retrieved from 1,003 patients. Stromal TILs were assessed on whole-section hematoxylin-eosin–stained slides using a dichotomized cutoff of 10%. Subtypes were scored using immunohistochemistry on tissue microarray. In total, 936 patients were evaluated. RESULTS Altogether, 670 (71%) of patients had TILs less than 10%. In a multivariable regression analysis with IBTR as dependent variable and RT, TILs, subtype, age, and grade as independent variables, RT (hazard ratio [HR], 0.42; 95% CI, 0.29 to 0.61; P < .001), high TILs (HR, 0.61; 95% CI, 0.39 to 0.96, P = .033) grade (3 v 1; HR, 2.17; 95% CI, 1.08 to 4.34; P = .029), and age (≥ 50 v < 50 years; HR, 0.55; 95% CI, 0.38 to 0.80; P = .002) were predictive of IBTR. RT was significantly beneficial in the low TILs group (HR, 0.37; 95% CI, 0.24 to 0.58; P < .001) but not in the high TILs group (HR, 0.58; 95% CI, 0.28 to 1.19; P = .138). The test for interaction between RT and TILs was not statistically significant ( P = .317). CONCLUSION This study shows that high values of TILs in the primary tumor independently seem to reduce the risk for an IBTR. Our findings further suggest that patients with breast cancer with low TILs may derive a larger benefit from RT regarding the risk of IBTR.
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Affiliation(s)
- Anikó Kovács
- Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Axel Stenmark Tullberg
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Erik Holmberg
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | | | - Dan Lundstedt
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Per Malmström
- Lund University, Lund, Sweden
- Skåne University Hospital, Lund, Sweden
| | | | - Per Karlsson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
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Prelaj A, Tay R, Ferrara R, Chaput N, Besse B, Califano R. Predictive biomarkers of response for immune checkpoint inhibitors in non-small-cell lung cancer. Eur J Cancer 2018; 106:144-159. [PMID: 30528799 DOI: 10.1016/j.ejca.2018.11.002] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 10/10/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022]
Abstract
Immune checkpoint blockade has been a pivotal development in the management of advanced non-small-cell lung cancer (NSCLC). Although durable antitumour activity and improved survival have been observed in a subset of patients, there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential non-responders. This review will address the use and limitations of tumour programmed death-ligand 1 expression as a predictive biomarker and review emerging biomarker strategies specifically related to NSCLC including genetic alterations (tumour mutation burden, loss and gain activated mutations), tumour-related factors (tumour microenvironment) and factors related to the host immune system. Novel approaches in biomarker detection such as peripheral blood monitoring will also be reviewed.
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Affiliation(s)
- Arsela Prelaj
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Department of Radiological, Pathological and Oncological Science, Sapienza University of Rome, Italy.
| | - Rebecca Tay
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
| | - Roberto Ferrara
- Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, Gustave Roussy, Villejuif, France.
| | - Nathalie Chaput
- Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, Gustave Roussy, Villejuif, France; Faculty of Pharmacy, University Paris-Saclay, Chatenay-Malabry, France.
| | - Benjamin Besse
- Cancer Medicine Department, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France.
| | - Raffaele Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Department of Medical Oncology, Manchester University NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK.
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10
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Curigliano G. Gyneco-oncological genomics and emerging biomarkers for cancer treatment with immune-checkpoint inhibitors. Semin Cancer Biol 2018; 52:253-258. [DOI: 10.1016/j.semcancer.2018.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 05/14/2018] [Indexed: 12/20/2022]
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11
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Bedognetti D, Roelands J, Decock J, Wang E, Hendrickx W. The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy. Emerg Top Life Sci 2017; 1:429-445. [PMID: 33525803 PMCID: PMC7289005 DOI: 10.1042/etls20170142] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/08/2017] [Accepted: 11/13/2017] [Indexed: 12/12/2022]
Abstract
With the advent of checkpoint inhibition, immunotherapy has revolutionized the clinical management of several cancers, but has demonstrated limited efficacy in mammary carcinoma. Transcriptomic profiling of cancer samples defined distinct immunophenotypic categories characterized by different prognostic and predictive connotations. In breast cancer, genomic alterations leading to the dysregulation of mitogen-activated protein kinase (MAPK) pathways have been linked to an immune-silent phenotype associated with poor outcome and treatment resistance. These aberrations include mutations of MAP3K1 and MAP2K4, amplification of KRAS, BRAF, and RAF1, and truncations of NF1. Anticancer therapies targeting MAPK signaling by BRAF and MEK inhibitors have demonstrated clear immunologic effects. These off-target properties could be exploited to convert the immune-silent tumor phenotype into an immune-active one. Preclinical evidence supports that MAPK-pathway inhibition can dramatically increase the efficacy of immunotherapy. In this review, we provide a detailed overview of the immunomodulatory impact of MAPK-pathway blockade through BRAF and MEK inhibitions. While BRAF inhibition might be relevant in melanoma only, MEK inhibition is potentially applicable to a wide range of tumors. Context-dependent similarities and differences of MAPK modulation will be dissected, in light of the complexity of the MAPK pathways. Therapeutic strategies combining the favorable effects of MAPK-oriented interventions on the tumor microenvironment while maintaining T-cell function will be presented. Finally, we will discuss recent studies highlighting the rationale for the implementation of MAPK-interference approaches in combination with checkpoint inhibitors and immune agonists in breast cancer.
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Affiliation(s)
- Davide Bedognetti
- Tumor Biology, Immunology, and Therapy Section, Department of Immunology, Inflammation and Metabolism, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar
- College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Jessica Roelands
- Tumor Biology, Immunology, and Therapy Section, Department of Immunology, Inflammation and Metabolism, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar
| | - Julie Decock
- Cancer Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Ena Wang
- Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar
| | - Wouter Hendrickx
- Tumor Biology, Immunology, and Therapy Section, Department of Immunology, Inflammation and Metabolism, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar
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12
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Single-cell mass cytometry and transcriptome profiling reveal the impact of graphene on human immune cells. Nat Commun 2017; 8:1109. [PMID: 29061960 PMCID: PMC5653675 DOI: 10.1038/s41467-017-01015-3] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 07/25/2017] [Indexed: 12/12/2022] Open
Abstract
Understanding the biomolecular interactions between graphene and human immune cells is a prerequisite for its utilization as a diagnostic or therapeutic tool. To characterize the complex interactions between graphene and immune cells, we propose an integrative analytical pipeline encompassing the evaluation of molecular and cellular parameters. Herein, we use single-cell mass cytometry to dissect the effects of graphene oxide (GO) and GO functionalized with amino groups (GONH2) on 15 immune cell populations, interrogating 30 markers at the single-cell level. Next, the integration of single-cell mass cytometry with genome-wide transcriptome analysis shows that the amine groups reduce the perturbations caused by GO on cell metabolism and increase biocompatibility. Moreover, GONH2 polarizes T-cell and monocyte activation toward a T helper-1/M1 immune response. This study describes an innovative approach for the analysis of the effects of nanomaterials on distinct immune cells, laying the foundation for the incorporation of single-cell mass cytometry on the experimental pipeline. Understanding the interaction of nanomaterials and immune cells at the biomolecular level is of great significance in therapeutic applications. Here, the authors investigated the interaction of graphene oxide nanomaterials and several immune cell subpopulations using single-cell mass cytometry and genome-wide transcriptome analysis.
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13
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Voong KR, Feliciano J, Becker D, Levy B. Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:376. [PMID: 29057236 PMCID: PMC5635257 DOI: 10.21037/atm.2017.06.48] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 06/08/2017] [Indexed: 12/26/2022]
Abstract
Recently, a firmer understanding of tumor immunology and tumor escape mechanisms has led to the development of immune checkpoint inhibitors, antibodies against programmed death-1 (PD-1) and its ligand (PD-L1). Nivolumab, pembrolizumab, and atezolizumab have dramatically altered the treatment paradigm in non-small cell lung cancer (NSCLC) and have each demonstrated improvements in outcomes and quality of life when compared to chemotherapy. Enrichment strategies to better select those patients more likely to respond have identified PD-L1 staining by immunohistochemistry (IHC) to be a predictive biomarker in both treatment naïve and refractory patients. Unfortunately, many challenges exist with this strategy and underscore the need for further exploration for more reliable biomarkers. Multiple tissue and plasma-based enrichment strategies have been identified in the hope of identifying patients more likely to benefit from checkpoint inhibitors. These include tumor mutational load; the "inflamed phenotype" including tumor infiltrating lymphocytes (TILS) and immunoscore; T-cell receptor clonality; gene signatures, and several plasma biomarkers. Several studies have revealed many of these biomarkers to be reliable predictors of response to immune checkpoint inhibitors across multiple tumor types. Given the small nature of these studies, additional prospective studies are warranted to formalize and validate each of these enrichment strategies.
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Affiliation(s)
- Khinh Ranh Voong
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Josephine Feliciano
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Daniel Becker
- Langone Cancer Center, Veterans Association Hospital, New York University, New York, NY, USA
| | - Benjamin Levy
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Sibley Memorial Hospital, Washington, DC, USA
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14
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Buschow SI, Ramazzotti M, Reinieren-Beeren IMJ, Heinzerling LM, Westdorp H, Stefanini I, Beltrame L, Hato SV, Ellebaek E, Gross S, Nguyen VA, Weinlich G, Ragoussis J, Baban D, Schuler-Thurner B, Svane IM, Romani N, Austyn JM, De Vries IJM, Schuler G, Cavalieri D, Figdor CG. Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein. Oncotarget 2017; 8:67439-67456. [PMID: 28978044 PMCID: PMC5620184 DOI: 10.18632/oncotarget.18698] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 05/22/2017] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (PEBP1)/Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low PEBP1 expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of PEBP1 after, but not prior to, DC vaccination. Moreover, the change in PEBP1 expression upon vaccination correlated well with survival. Further analyses revealed that PEBP1 expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including STAT3, NOTCH1, and MAPK1. Concordantly, PEBP1 inversely correlated with the myeloid/lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.
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Affiliation(s)
- Sonja I Buschow
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Gastroenterology and Hepatology, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands
| | - Matteo Ramazzotti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Inge M J Reinieren-Beeren
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lucie M Heinzerling
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Harm Westdorp
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Irene Stefanini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Luca Beltrame
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Stanleyson V Hato
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eva Ellebaek
- CCIT, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Stefanie Gross
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Van Anh Nguyen
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Weinlich
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jiannis Ragoussis
- Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.,Current address: McGill University and Genome Quebec Innovation Centre, McGill University, Quebec, Canada
| | - Dilair Baban
- Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Beatrice Schuler-Thurner
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Inge M Svane
- CCIT, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Nikolaus Romani
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jonathan M Austyn
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - I Jolanda M De Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gerold Schuler
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | | | - Carl G Figdor
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Hendrickx W, Simeone I, Anjum S, Mokrab Y, Bertucci F, Finetti P, Curigliano G, Seliger B, Cerulo L, Tomei S, Delogu LG, Maccalli C, Wang E, Miller LD, Marincola FM, Ceccarelli M, Bedognetti D. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology 2017; 6:e1253654. [PMID: 28344865 PMCID: PMC5353940 DOI: 10.1080/2162402x.2016.1253654] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/20/2016] [Accepted: 10/22/2016] [Indexed: 12/20/2022] Open
Abstract
Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity.
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Affiliation(s)
- Wouter Hendrickx
- Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar
| | - Ines Simeone
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar; Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Samreen Anjum
- Qatar Computing Research Institute, Hamad Bin Khalifa University , Doha, Qatar
| | - Younes Mokrab
- Division of Biomedical Informatics, Research Branch, Sidra Medical and Research Center , Doha, Qatar
| | - François Bertucci
- Département d'Oncologie Moléculaire, Center de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France; Département d'Oncologie Médicale, CRCM, Institut Paoli-Calmettes, Marseille, France; Faculté de Médecine, Aix-Marseille Université, Marseille, France
| | - Pascal Finetti
- Département d'Oncologie Moléculaire, Center de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes , INSERM UMR1068, CNRS UMR725 , Marseille, France
| | - Giuseppe Curigliano
- Division of Experimental Therapeutics, Division of Medical Oncology, European Institute of Oncology , Milan, Italy
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg , Halle, Germany
| | - Luigi Cerulo
- Department of Science and Technology, University of Sannio, Benevento, Italy; BIOGEM Research Center, Ariano Irpino, Italy
| | - Sara Tomei
- Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar
| | - Lucia Gemma Delogu
- Department of Chemistry and Pharmacy, University of Sassari , Sassari, Italy
| | - Cristina Maccalli
- Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar
| | - Ena Wang
- Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar
| | - Lance D Miller
- Department of Cancer Biology, Wake Forest School of Medicine , Winston-Salem, NC, USA
| | - Francesco M Marincola
- Office of the Chief Research Officer (CRO), Research Branch, Sidra Medical and Research Center , Doha, Qatar
| | - Michele Ceccarelli
- Qatar Computing Research Institute, Hamad Bin Khalifa University , Doha, Qatar
| | - Davide Bedognetti
- Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar
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16
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Orecchioni M, Ménard-Moyon C, Delogu LG, Bianco A. Graphene and the immune system: Challenges and potentiality. Adv Drug Deliv Rev 2016; 105:163-175. [PMID: 27235665 DOI: 10.1016/j.addr.2016.05.014] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/07/2016] [Accepted: 05/17/2016] [Indexed: 11/19/2022]
Abstract
In the growing area of nanomedicine, graphene-based materials (GBMs) are some of the most recent explored nanomaterials. For the majority of GBM applications in nanomedicine, the immune system plays a fundamental role. It is necessary to well understand the complexity of the interactions between GBMs, the immune cells, and the immune components and how they could be of advantage for novel effective diagnostic and therapeutic approaches. In this review, we aimed at painting the current picture of GBMs in the background of the immune system. The picture we have drawn looks like a cubist image, a sort of Picasso-like portrait looking at the topic from all perspectives: the challenges (due to the potential toxicity) and the potentiality like the conjugation of GBMs to biomolecules to develop advanced nanomedicine tools. In this context, we have described and discussed i) the impact of graphene on immune cells, ii) graphene as immunobiosensor, and iii) antibodies conjugated to graphene for tumor targeting. Thanks to the huge advances on graphene research, it seems realistic to hypothesize in the near future that some graphene immunoconjugates, endowed of defined immune properties, can go through preclinical test and be successfully used in nanomedicine.
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Affiliation(s)
- Marco Orecchioni
- Department of Chemistry and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Cécilia Ménard-Moyon
- CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et de Chimie Thérapeutique, 67000 Strasbourg, France
| | - Lucia Gemma Delogu
- Department of Chemistry and Pharmacy, University of Sassari, 07100 Sassari, Italy.
| | - Alberto Bianco
- CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et de Chimie Thérapeutique, 67000 Strasbourg, France.
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17
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Fischbacher D, Merle M, Liepert A, Grabrucker C, Kroell T, Kremser A, Dreyßig J, Freudenreich M, Schuster F, Borkhardt A, Kraemer D, Koehne CH, Kolb HJ, Schmid C, Schmetzer HM. Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy. ACTA ACUST UNITED AC 2016; 22:49-65. [DOI: 10.1080/15419061.2016.1223634] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Dorothea Fischbacher
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Marion Merle
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Anja Liepert
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Christine Grabrucker
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Tanja Kroell
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Andreas Kremser
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Julia Dreyßig
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Markus Freudenreich
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
| | - Friedhelm Schuster
- Department for pediatric Haematology and Oncology, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Arndt Borkhardt
- Department for pediatric Haematology and Oncology, University Hospital of Düsseldorf, Düsseldorf, Germany
| | | | | | - Hans-Jochem Kolb
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
- Helmholtz Center, Munich, Clinical cooperative group Human Cell Transplantation (CCG-HCT), Munich, Germany
| | | | - Helga Maria Schmetzer
- Department for Haematopoietic Transplantations, University Hospital of Munich, Munich, Germany
- Helmholtz Center, Munich, Clinical cooperative group Human Cell Transplantation (CCG-HCT), Munich, Germany
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18
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Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases. Cancer Immunol Immunother 2016; 65:1189-99. [PMID: 27522581 DOI: 10.1007/s00262-016-1881-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 07/11/2016] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases. PATIENTS AND METHODS Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. RESULTS Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. CONCLUSION The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.
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Chheda ZS, Sharma RK, Jala VR, Luster AD, Haribabu B. Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors. THE JOURNAL OF IMMUNOLOGY 2016; 197:2016-26. [PMID: 27465528 DOI: 10.4049/jimmunol.1502376] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 06/26/2016] [Indexed: 12/29/2022]
Abstract
Immunotherapies have shown considerable efficacy for the treatment of various cancers, but a multitude of patients remain unresponsive for various reasons, including poor homing of T cells into tumors. In this study, we investigated the roles of the leukotriene B4 receptor, BLT1, and CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, under endogenous as well as vaccine-induced antitumor immune response in a syngeneic murine model of B16 melanoma. Significant accelerations in tumor growth and reduced survival were observed in both BLT1(-/-) and CXCR3(-/-) mice as compared with wild-type (WT) mice. Analysis of tumor-infiltrating leukocytes revealed significant reduction of CD8(+) T cells in the tumors of BLT1(-/-) and CXCR3(-/-) mice as compared with WT tumors, despite their similar frequencies in the periphery. Adoptive transfer of WT but not BLT1(-/-) or CXCR3(-/-) CTLs significantly reduced tumor growth in Rag2(-/-) mice, a function attributed to reduced infiltration of knockout CTLs into tumors. Cotransfer experiments suggested that WT CTLs do not facilitate the infiltration of knockout CTLs to tumors. Anti-programmed cell death-1 (PD-1) treatment reduced the tumor growth rate in WT mice but not in BLT1(-/-), CXCR3(-/-), or BLT1(-/-)CXCR3(-/-) mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti-PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti-PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies.
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Affiliation(s)
- Zinal S Chheda
- James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville Health Sciences, Louisville, KY 40202
| | - Rajesh K Sharma
- James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Division of Medical Oncology, Department of Medicine, University of Louisville Health Sciences, Louisville, KY 40202; and
| | - Venkatakrishna R Jala
- James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville Health Sciences, Louisville, KY 40202
| | - Andrew D Luster
- Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139
| | - Bodduluri Haribabu
- James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville Health Sciences, Louisville, KY 40202;
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Abstract
PURPOSE OF REVIEW Here, we focus on molecular biomarkers derived from transcriptomic studies to summarize the recent advances in our understanding of the mechanisms associated with differential prognosis and treatment outcome in breast cancer. RECENT FINDINGS Breast cancer is certainly immunogenic; yet it has been historically resistant to immunotherapy. In the past few years, refined immunotherapeutic manipulations have been shown to be effective in a significant proportion of cancer patients. For example, drugs targeting the PD-1 immune checkpoint have been proven to be an effective therapeutic approach in several solid tumors including melanoma and lung cancer. Very recently, the activity of such therapeutics has also been demonstrated in breast cancer patients. Pari passu with the development of novel immune modulators, the transcriptomic analysis of human tumors unveiled unexpected and paradoxical relationships between cancer cells and immune cells. SUMMARY This review examines our understanding of the molecular pathways associated with intratumoral immune response, which represents a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of breast cancer.
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21
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Jin P, Zhao Y, Liu H, Chen J, Ren J, Jin J, Bedognetti D, Liu S, Wang E, Marincola F, Stroncek D. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype. Sci Rep 2016; 6:26345. [PMID: 27211104 PMCID: PMC4876328 DOI: 10.1038/srep26345] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/26/2016] [Indexed: 01/21/2023] Open
Abstract
Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment.
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Affiliation(s)
- Ping Jin
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
| | - Yuanlong Zhao
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
| | - Hui Liu
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
| | - Jinguo Chen
- Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jiaqiang Ren
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
| | - Jianjian Jin
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
| | | | - Shutong Liu
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
| | - Ena Wang
- Research Branch, Sidra Medical and Research Center, Doha, Qatar
| | | | - David Stroncek
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 USA
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22
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Guennoun A, Sidahmed H, Maccalli C, Seliger B, Marincola FM, Bedognetti D. Harnessing the immune system for the treatment of melanoma: current status and future prospects. Expert Rev Clin Immunol 2016; 12:879-93. [PMID: 27070898 DOI: 10.1080/1744666x.2016.1176529] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
When malignant melanoma is diagnosed early, surgical resection is the intervention of choice and is often curative, but many patients present with unresectable disease at later stages. Due to its complex etiology paired with well-documented chemoresistance and high metastatic potential, patients with advanced melanoma had a poor prognosis, and the treatment of this disease remained unsatisfactory for many years. Recently, targeted therapy, immune checkpoint inhibition, or combinatory approaches have revolutionized the therapeutic options of melanoma allowing considerable improvement in disease control and survival. In this review we will summarize these novel therapeutic strategies with particular focus on combinatory immunotherapies and further discuss recent data derived from immunogenomic studies and potential options to improve the therapeutic efficacy of immune modulatory approaches.
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Affiliation(s)
- Andrea Guennoun
- a Division of Translational Medicine , Research Branch, Sidra Medical and Research Center , Doha , Qatar
| | - Heba Sidahmed
- a Division of Translational Medicine , Research Branch, Sidra Medical and Research Center , Doha , Qatar
| | - Cristina Maccalli
- b Tumor Biology, Immunology and Therapy Section, Division of Translational Medicine , Research Branch, Sidra Medical and Research Center , Doha , Qatar
| | - Barbara Seliger
- c Institute of Medical Immunology , Martin Luther University Halle-Wittenberg , Halle , Germany
| | - Francesco M Marincola
- d Office of the Chief Research Officer (CRO) , Research Branch, Sidra Medical and Research Center , Doha , Qatar
| | - Davide Bedognetti
- b Tumor Biology, Immunology and Therapy Section, Division of Translational Medicine , Research Branch, Sidra Medical and Research Center , Doha , Qatar
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Bedognetti D, Maccalli C, Bader SBA, Marincola FM, Seliger B. Checkpoint Inhibitors and Their Application in Breast Cancer. Breast Care (Basel) 2016; 11:108-15. [PMID: 27239172 PMCID: PMC4881248 DOI: 10.1159/000445335] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.
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Affiliation(s)
- Davide Bedognetti
- Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar
| | - Cristina Maccalli
- Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar
| | - Salha B.J. Al Bader
- National Center for Cancer Care and Research (NCCCR), and Hamad General Hospital, Doha, Qatar
| | - Francesco M. Marincola
- Office of the Chief Research Officer (CRO), Sidra Medical and Research Center, Doha, Qatar
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
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24
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Kohrt HE, Tumeh PC, Benson D, Bhardwaj N, Brody J, Formenti S, Fox BA, Galon J, June CH, Kalos M, Kirsch I, Kleen T, Kroemer G, Lanier L, Levy R, Lyerly HK, Maecker H, Marabelle A, Melenhorst J, Miller J, Melero I, Odunsi K, Palucka K, Peoples G, Ribas A, Robins H, Robinson W, Serafini T, Sondel P, Vivier E, Weber J, Wolchok J, Zitvogel L, Disis ML, Cheever MA. Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials. J Immunother Cancer 2016; 4:15. [PMID: 26981245 PMCID: PMC4791805 DOI: 10.1186/s40425-016-0118-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/15/2016] [Indexed: 12/26/2022] Open
Abstract
The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.
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Affiliation(s)
- Holbrook E Kohrt
- Division of Oncology, Stanford Cancer Institute, Stanford University Medical Center, 269 Campus Drive, CCSR 1105, Stanford, CA 94305-5151 USA
| | - Paul C Tumeh
- Division of Dermatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA USA
| | - Don Benson
- Division of Hematology/Oncology, Ohio State University, Columbus, OH USA
| | - Nina Bhardwaj
- Medicine, Hematology and Medical Oncology, Mount Sinai Hospital, New York, NY USA
| | - Joshua Brody
- Medicine, Hematology and Medical Oncology, Mount Sinai Hospital, Ruttenberg Treatment Center, New York, NY USA
| | - Silvia Formenti
- Department of Radiation Oncology, New York Weill Cornell Medical Center, New York, NY USA
| | - Bernard A Fox
- SOM-Molecular Microbiology & Immunology Department, Laboratory of Molecular and Tumor Immunology, OHSU Cancer Institute, Portland, OR USA
| | - Jerome Galon
- INSERM, Integrative Cancer Immunology Team, Cordeliers Research Center, Paris, France
| | - Carl H June
- Perelman School of Medicine, University of Pennsylvania, Pathology and Laboratory Medicine, Philadelphia, PA USA
| | - Michael Kalos
- Cancer Immunobiology, Eli Lilly & Company, New York, NY USA
| | - Ilan Kirsch
- Translational Medicine, Adaptive Biotechnologies Corp, Seattle, WA USA
| | - Thomas Kleen
- Immune Monitoring, Epiontis GmbH, Berlin, Germany
| | - Guido Kroemer
- Faculty of Medicine, University of Paris Descartes, Paris, France
| | - Lewis Lanier
- Department of Microbiology and Immunology, University of California, San Francisco, CA USA
| | - Ron Levy
- Division of Oncology, Stanford School of Medicine, Stanford, CA USA
| | - H Kim Lyerly
- Duke University School of Medicine, Durham, NC USA
| | - Holden Maecker
- Human Immune Monitoring Center Shared Resource, Stanford Cancer Institute, Stanford, CA USA
| | | | - Jos Melenhorst
- Product Development and Correlative Sciences, Smilow Center for Translational Research, Philadelphia, PA USA
| | - Jeffrey Miller
- Division of Hematology, Experimental Therapeutics, University of Minnesota, Oncology and Transplantation, Minneapolis, MN USA
| | - Ignacio Melero
- Centro de Investigacion Medica Aplicada, Universidad de Navarra, Avda. Pamplona, Spain
| | - Kunle Odunsi
- Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY USA
| | | | - George Peoples
- Cancer Vaccine Development Program, Brooke Army Medical Center, Houston, TX USA
| | - Antoni Ribas
- Tumor Immunology Program Area, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA USA
| | | | - William Robinson
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
| | | | - Paul Sondel
- Cellular & Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI USA
| | - Eric Vivier
- Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | | | - Jedd Wolchok
- Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY USA
| | - Laurence Zitvogel
- Institut National de la Santé et Recherche Médicale, Institut GrustaveRoussy, Villejuif, France
| | - Mary L Disis
- Tumor Vaccine Group, University of Washington, Seattle, WA USA
| | - Martin A Cheever
- Fred Hutchinson Cancer Research Center, 1100 Eastlake Ave N., E3-300, PO Box 19024, Seattle, WA 98109-1023 USA
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Bedognetti D, Hendrickx W, Ceccarelli M, Miller LD, Seliger B. Disentangling the relationship between tumor genetic programs and immune responsiveness. Curr Opin Immunol 2016; 39:150-8. [PMID: 26967649 DOI: 10.1016/j.coi.2016.02.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/03/2016] [Accepted: 02/04/2016] [Indexed: 12/13/2022]
Abstract
Correlative studies in humans have demonstrated that an active immune microenvironment characterized by the presence of a T-helper 1 immune response typifies a tumor phenotype associated with better outcome and increased responsiveness to immune manipulation. This phenotype also signifies the counter activation of immune-regulatory mechanisms. Variables modulating the development of an effective anti-tumor immune response are increasingly scrutinized as potential therapeutic targets. Genetic alterations of cancer cells that functionally influence intratumoral immune response include mutational load, specific mutations of genes involved in oncogenic pathways and copy number aberrations involving chemokine and cytokine genes. Inhibiting oncogenic pathways that prevent the development of the immune-favorable cancer phenotype may complement modern immunotherapeutic approaches.
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Affiliation(s)
- Davide Bedognetti
- Tumor Biology, Immunology and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
| | - Wouter Hendrickx
- Tumor Biology, Immunology and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar
| | - Michele Ceccarelli
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Lance D Miller
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
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26
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Orecchioni M, Jasim DA, Pescatori M, Manetti R, Fozza C, Sgarrella F, Bedognetti D, Bianco A, Kostarelos K, Delogu LG. Molecular and Genomic Impact of Large and Small Lateral Dimension Graphene Oxide Sheets on Human Immune Cells from Healthy Donors. Adv Healthc Mater 2016; 5:276-87. [PMID: 26687729 DOI: 10.1002/adhm.201500606] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Revised: 09/04/2015] [Indexed: 12/13/2022]
Abstract
Graphene oxide (GO) is attracting great interest in biomedical sciences. The impact of GO on immune cells is one fundamental area of study that is often overlooked, but critical in terms of clinical translation. This work investigates the effects of two types of thoroughly characterized GO sheets, different in their lateral dimension, on human peripheral immune cells provided from healthy donors using a wide range of assays. After evaluation of cell viability, the gene expression was analyzed, following GO exposure on 84 genes related to innate and adaptive immune responses. Exposure to GO small sheets was found to have a more significant impact on immune cells compared to GO large sheets, reflected in the upregulation of critical genes implicated in immune responses and the release of cytokines IL1β and TNFα. These findings were further confirmed by whole-genome microarray analysis of the impact of small GO sheets on T cells and monocytes. Activation in both cell types was underlined by the overexpression of genes such as CXCL10 and receptor CXCR3. Significant energy-dependent pathway modulation was identified. These findings can potentially pave the foundations for further design of graphene that can be used for immune modulation applications, for example in cancer immunotherapy.
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Affiliation(s)
- Marco Orecchioni
- Department of Chemistry and Pharmacy; University of Sassari; 07100 Sassari Italy
| | - Dhifaf A. Jasim
- Nanomedicine Lab; Faculty of Medical and Human Sciences; The University of Manchester; Manchester M13 9PT UK
| | - Mario Pescatori
- Department of Chemistry and Pharmacy; University of Sassari; 07100 Sassari Italy
- Heath-E-Solutions; Rotterdam 3016 DL The Netherlands
| | - Roberto Manetti
- Department of Clinical Medicine and Experimental Oncology; University of Sassari; 07100 Sassari Italy
| | - Claudio Fozza
- Department of Biomedical Science; University of Sassari; 07100 Sassari Italy
| | - Francesco Sgarrella
- Department of Chemistry and Pharmacy; University of Sassari; 07100 Sassari Italy
| | | | - Alberto Bianco
- CNRS; Institut de Biologie Moléculaire et Cellulaire; Laboratorie d'Immunopathologie et Chimie Thérapeutique; 67000 Strasbourg France
| | - Kostas Kostarelos
- Nanomedicine Lab; Faculty of Medical and Human Sciences; The University of Manchester; Manchester M13 9PT UK
| | - Lucia Gemma Delogu
- Department of Chemistry and Pharmacy; University of Sassari; 07100 Sassari Italy
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27
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Furman D, Davis MM. New approaches to understanding the immune response to vaccination and infection. Vaccine 2015; 33:5271-81. [PMID: 26232539 DOI: 10.1016/j.vaccine.2015.06.117] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/26/2015] [Accepted: 06/29/2015] [Indexed: 02/06/2023]
Abstract
The immune system is a network of specialized cell types and tissues that communicates via cytokines and direct contact, to orchestrate specific types of defensive responses. Until recently, we could only study immune responses in a piecemeal, highly focused fashion, on major components like antibodies to the pathogen. But recent advances in technology and in our understanding of the many components of the system, innate and adaptive, have made possible a broader approach, where both the multiple responding cells and cytokines in the blood are measured. This systems immunology approach to a vaccine response or an infection gives us a more holistic picture of the different parts of the immune system that are mobilized and should allow us a much better understanding of the pathways and mechanisms of such responses, as well as to predict vaccine efficacy in different populations well in advance of efficacy studies. Here we summarize the different technologies and methods and discuss how they can inform us about the differences between diseases and vaccines, and how they can greatly accelerate vaccine development.
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Affiliation(s)
- David Furman
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, United States; Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Mark M Davis
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, United States; Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, United States; Howard Hughes Medical Institute, School of Medicine, Stanford University, Stanford, CA, United States.
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28
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Lyday B, Chen T, Kesari S, Minev B. Overcoming tumor immune evasion with an unique arbovirus. J Transl Med 2015; 13:3. [PMID: 25592450 PMCID: PMC4307212 DOI: 10.1186/s12967-014-0349-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 12/01/2014] [Indexed: 12/02/2022] Open
Abstract
Combining dendritic cell vaccination with the adjuvant effect of a strain of dengue virus may be a way to overcome known tumor immune evasion mechanisms. Dengue is unique among viruses as primary infections carry lower mortality than the common cold, but secondary infections carry significant risk of hypovolemic shock. While current immuno-therapies rely on a single axis of attack, this approach combines physiological (hyperthermic reduction of tumor perfusion), immunological (activation of effector cells of the adaptive and innate immune system), and apoptosis-inducing pathways (sTRAIL) to destroy tumor cells. The premise of using multiple mechanisms of action in synergy with a decline in the ability of the tumor cells to employ resistance methods suggests the potential of this combination approach in cancer immunotherapy.
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Affiliation(s)
| | | | - Santosh Kesari
- Department of Neurosciences, Translational Neuro-Oncology Laboratories, UC San Diego, La Jolla, CA, 92093, USA. .,Moores UCSD Cancer Center, UC San Diego, La Jolla, CA, 92093, USA.
| | - Boris Minev
- Moores UCSD Cancer Center, UC San Diego, La Jolla, CA, 92093, USA. .,Division of Neurosurgery, UC San Diego, La Jolla, CA, 92093, USA. .,Genelux Corporation, San Diego Science Center, San Diego, CA, 92109, USA.
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29
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Sharma RK, Chheda ZS, Jala VR, Haribabu B. Regulation of cytotoxic T-Lymphocyte trafficking to tumors by chemoattractants: implications for immunotherapy. Expert Rev Vaccines 2014; 14:537-49. [PMID: 25482400 DOI: 10.1586/14760584.2015.982101] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cancer immunotherapy has recently emerged as an important treatment modality. FDA approval of provenge, ipilimumab and pembrolizumab has started to deliver on the long awaited promise of cancer immunotherapy. Many new modalities of immunotherapies targeting cytotoxic T lymphocytes (CTLs) responses, such as adoptive cell therapies and vaccines, are in advanced clinical trials. In all these immunotherapies, migration of CTLs to the tumor site is a critical step for achieving therapeutic efficacy. However, inefficient infiltration of activated CTLs into established tumors is increasingly being recognized as one of the major hurdles limiting efficacy. Mechanisms that control migration of CTLs to tumors are poorly defined. In this review, the authors discuss the chemoattractants and their receptors that have been implicated in endogenous- or immunotherapy-induced CTL recruitment to tumors and the potential for targeting these pathways for therapeutic efficacy.
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Affiliation(s)
- Rajesh K Sharma
- James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202, USA
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30
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Baxevanis CN, Anastasopoulou EA, Voutsas IF, Papamichail M, Perez SA. Immune biomarkers: how well do they serve prognosis in human cancers? Expert Rev Mol Diagn 2014; 15:49-59. [PMID: 25345403 DOI: 10.1586/14737159.2015.965684] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In order to be optimally efficacious, therapeutic cancer vaccines must induce robust tumor-specific CD8(+) cytotoxic T cells, which are responsible for tumor cell lysis. Unlike cytotoxic drugs, which act directly on the tumor, cancer vaccines demonstrate new kinetics involving the generation of specific cellular immune responses, which need to be translated into antitumor responses to delay tumor progression and improve survival. These delayed kinetics of action establish a new concept of benefit in the long term, which implies a slow down in tumor growth rates, than a marked reduction in tumor size. Therefore, there is a significant need to identify intermediate biomarkers so that clinical responses can be evaluated in a timely manner. Therapeutic vaccination as a modality for cancer treatment has received significant attention with multiple clinical trials demonstrating improvements in overall survival. Significant challenges to this modality remain, including increasing vaccine potency and minimizing treatment-related toxicities and identifying prognostic and predictive biomarkers of clinical benefit that may guide to select and optimize the therapeutic strategies for patients most likely to gain benefit.
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Affiliation(s)
- Constantin N Baxevanis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, Athens 11522, Greece
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31
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Direct T cell-tumour interaction triggers TH1 phenotype activation through the modification of the mesenchymal stromal cells transcriptional programme. Br J Cancer 2014; 110:2955-64. [PMID: 24809778 PMCID: PMC4056054 DOI: 10.1038/bjc.2014.235] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/18/2014] [Accepted: 04/09/2014] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are heterogeneous cells with immunoregulatory and wound-healing properties. In cancer, they are known to be an essential part of the tumour microenvironment. However, their role in tumour growth and rejection remains unclear. To investigate this, we co-cultured human MSCs, tumour infiltrating lymphocytes (TIL), and melanoma cells to investigate the role of MSCs in the tumour environment. METHODS Mesenchymal stromal cells were co-cultured with melanoma antigen-specific TIL that were stimulated either with HLA-A*0201(+) melanoma cells or with a corresponding clone that had lost HLA-A*0201 expression. RESULTS Activated TIL induced profound pro-inflammatory gene expression signature in MSCs. Analysis of culture supernatant found that MSCs secreted pro-inflammatory cytokines, including TH1 cytokines that have been previously associated with immune-mediated antitumor responses. In addition, immunohistochemical analysis on selected markers revealed that the same activated MSCs secreted both the TH1 cytokine (interleukin-12) and indoleamine 2,3 dioxygenase (IDO), a classical immunosuppressive factor. CONCLUSIONS This study reflected that the plasticity of MSCs is highly dependent upon microenvironment conditions. Tumour-activated TIL induced TH1 phenotype change in MSCs that is qualitatively similar to the previously described immunologic constant of rejection signature observed during immune-mediated, tissue-specific destruction. This response may be responsible for the in loco amplification of antigen-specific anti-cancer immune response.
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32
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Hailemichael Y, Overwijk WW. Cancer vaccines: Trafficking of tumor-specific T cells to tumor after therapeutic vaccination. Int J Biochem Cell Biol 2014; 53:46-50. [PMID: 24796845 DOI: 10.1016/j.biocel.2014.04.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 04/23/2014] [Accepted: 04/25/2014] [Indexed: 01/17/2023]
Abstract
Cancer vaccines can induce robust activation of tumor-specific CD8(+) T cells that can destroy tumors. Understanding the mechanism by which cancer vaccines work is essential in designing next-generation vaccines with more potent therapeutic activity. We recently reported that short peptides emulsified in poorly biodegradable, Incomplete Freund's Adjuvant (IFA) primed CD8(+) T cells that did not localize to the tumor site but accumulated at the persisting, antigen-rich vaccination site. The vaccination site eventually became a T cell graveyard where T cells responded to chronically released gp100 peptide by releasing cytokines, including interferon-γ (IFN-γ), which in turn upregulated Fas ligand (FasL) on host cells, causing apoptosis of Fas(+) T cells. T cells that escaped apoptosis rapidly became exhausted, memory formation was poor, and therapeutic impact was minimal. Replacing the non-biodegradable IFA-based formulation with water-based, short-lived formulation in the presence of immunostimulatory molecules allowed T cells to traffic to tumors, causing their regression. In this review, we discuss recent advances in immunotherapeutic approaches that could enhance vaccine-primed immune cells fitness and render the tumor microenvironment more accessible for immune cell infiltration.
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Affiliation(s)
- Yared Hailemichael
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Willem W Overwijk
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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33
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Bedognetti D, Wang E, Marincola FM. Meta-analysis and metagenes: CXCL-13-driven signature as a robust marker of intratumoral immune response and predictor of breast cancer chemotherapeutic outcome. Oncoimmunology 2014; 3:e28727. [PMID: 25340012 PMCID: PMC4203509 DOI: 10.4161/onci.28727] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 03/01/2014] [Indexed: 12/15/2022] Open
Affiliation(s)
- Davide Bedognetti
- Infectious Disease and Immunogenetics Section; Department of Transfusion Medicine; Clinical Center and Trans-NIH Center for Human Immunology; National Institutes of Health; Bethesda, MD USA
| | - Ena Wang
- Infectious Disease and Immunogenetics Section; Department of Transfusion Medicine; Clinical Center and Trans-NIH Center for Human Immunology; National Institutes of Health; Bethesda, MD USA ; Research Branch; Sidra Medical and Research Centre; Doha, Qatar
| | - Francesco M Marincola
- Infectious Disease and Immunogenetics Section; Department of Transfusion Medicine; Clinical Center and Trans-NIH Center for Human Immunology; National Institutes of Health; Bethesda, MD USA ; Research Branch; Sidra Medical and Research Centre; Doha, Qatar
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34
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Tomei S, Wang E, Delogu LG, Marincola FM, Bedognetti D. Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma. Expert Opin Biol Ther 2014; 14:663-86. [DOI: 10.1517/14712598.2014.890586] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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35
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Matsueda S, Graham DY. Immunotherapy in gastric cancer. World J Gastroenterol 2014; 20:1657-1666. [PMID: 24587645 PMCID: PMC3930966 DOI: 10.3748/wjg.v20.i7.1657] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/15/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the second most common of cancer-related deaths worldwide. In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved, survival rates remain poor. Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer, prostate cancer and melanoma. Here, we provide an overview of concepts of modern cancer immunotherapy including the theory, current approaches, remaining hurdles to be overcome, and the future prospect of cancer immunotherapy in the treatment of gastric cancer. Adaptive cell therapies, cancer vaccines, gene therapies, monoclonal antibody therapies have all been used with some initial successes in gastric cancer. However, to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response. Here, we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy. We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment. We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells. Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being. Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright.
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36
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Azuma K, Komatsu N, Hattori S, Matsueda S, Kawahara A, Sasada T, Itoh K, Hoshino T. Humoral immune responses to EGFR-derived peptides predict progression-free and overall survival of non-small cell lung cancer patients receiving gefitinib. PLoS One 2014; 9:e86667. [PMID: 24497964 PMCID: PMC3909003 DOI: 10.1371/journal.pone.0086667] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 12/12/2013] [Indexed: 11/19/2022] Open
Abstract
Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, in patients with non-small cell lung cancer (NSCLC). However, humoral immune responses to EGFR in NSCLC patients have not been well studied. In this study, we investigated the clinical significance of immunoglobulin G (IgG) responses to EGFR-derived peptides in NSCLC patients receiving gefitinib. Plasma IgG titers to each of 60 different EGFR-derived 20-mer peptides were measured by the Luminex system in 42 NSCLC patients receiving gefitinib therapy. The relationships between the peptide-specific IgG titers and presence of EGFR mutations or patient survival were evaluated statistically. IgG titers against the egfr_481–500, egfr_721–740, and egfr_741–760 peptides were significantly higher in patients with exon 21 mutation than in those without it. On the other hand, IgG titers against the egfr_841–860 and egfr_1001–1020 peptides were significantly lower and higher, respectively, in patients with deletion in exon 19. Multivariate Cox regression analysis showed that IgG responses to egfr_41_ 60, egfr_61_80 and egfr_481_500 were significantly prognostic for progression-free survival independent of other clinicopathological characteristics, whereas those to the egfr_41_60 and egfr_481_500 peptides were significantly prognostic for overall survival. Detection of IgG responses to EGFR-derived peptides may be a promising method for prognostication of NSCLC patients receiving gefitinib. Our results may provide new insight for better understanding of humoral responses to EGFR in NSCLC patients.
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Affiliation(s)
- Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
- * E-mail:
| | - Nobukazu Komatsu
- Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Satoshi Hattori
- Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan
| | - Satoko Matsueda
- Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Akihiko Kawahara
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka, Japan
| | - Tetsuro Sasada
- Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Kyogo Itoh
- Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Tomoaki Hoshino
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. Br J Cancer 2013; 109:2412-23. [PMID: 24129241 PMCID: PMC3817317 DOI: 10.1038/bjc.2013.557] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 08/19/2013] [Accepted: 08/20/2013] [Indexed: 01/10/2023] Open
Abstract
Background: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. Methods: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). Results: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. Conclusion: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.
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The Continuum of Cancer Immunosurveillance: Prognostic, Predictive, and Mechanistic Signatures. Immunity 2013; 39:11-26. [DOI: 10.1016/j.immuni.2013.07.008] [Citation(s) in RCA: 600] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 07/09/2013] [Indexed: 11/21/2022]
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Functionalized carbon nanotubes as immunomodulator systems. Biomaterials 2013; 34:4395-403. [DOI: 10.1016/j.biomaterials.2013.02.052] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 02/19/2013] [Indexed: 12/12/2022]
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Dominguez MH, Chattopadhyay PK, Ma S, Lamoreaux L, McDavid A, Finak G, Gottardo R, Koup RA, Roederer M. Highly multiplexed quantitation of gene expression on single cells. J Immunol Methods 2013; 391:133-45. [PMID: 23500781 PMCID: PMC3814038 DOI: 10.1016/j.jim.2013.03.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 03/04/2013] [Accepted: 03/04/2013] [Indexed: 01/12/2023]
Abstract
Highly multiplexed, single-cell technologies reveal important heterogeneity within cell populations. Recently, technologies to simultaneously measure expression of 96 (or more) genes from a single cell have been developed for immunologic monitoring. Here, we report a rigorous, optimized, quantitative methodology for using this technology. Specifically: we describe a unique primer/probe qualification method necessary for quantitative results; we show that primers do not compete in highly multiplexed amplifications; we define the limit of detection for this assay as a single mRNA transcript; and, we show that the technical reproducibility of the system is very high. We illustrate two disparate applications of the platform: a "bulk" approach that measures expression patterns from 100 cells at a time in high throughput to define gene signatures, and a single-cell approach to define the coordinate expression patterns of multiple genes and reveal unique subsets of cells.
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Affiliation(s)
- Maria H. Dominguez
- ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, United States
| | | | - Steven Ma
- Laboratory of Immunology, Vaccine Research Center, NIAID, NIH, United States
| | - Laurie Lamoreaux
- Laboratory of Immunology, Vaccine Research Center, NIAID, NIH, United States
| | - Andrew McDavid
- Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Public Health Sciences Division, University of Washington, United States
| | - Greg Finak
- Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Public Health Sciences Division, University of Washington, United States
| | - Raphael Gottardo
- Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Public Health Sciences Division, University of Washington, United States
| | - Richard A. Koup
- Laboratory of Immunology, Vaccine Research Center, NIAID, NIH, United States
| | - Mario Roederer
- ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, United States
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Wang E, Bedognetti D, Marincola FM. Prediction of response to anticancer immunotherapy using gene signatures. J Clin Oncol 2013; 31:2369-71. [PMID: 23715576 DOI: 10.1200/jco.2013.49.2157] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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Liu L, Zhang Y, Wang J, Zhao H, Jiang L, Che Y, Shi H, Li R, Mo Z, Huang T, Liang Z, Mao Q, Wang L, Dong C, Liao Y, Guo L, Yang E, Pu J, Yue L, Zhou Z, Li Q. Study of the integrated immune response induced by an inactivated EV71 vaccine. PLoS One 2013; 8:e54451. [PMID: 23372725 PMCID: PMC3553120 DOI: 10.1371/journal.pone.0054451] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Accepted: 12/11/2012] [Indexed: 12/12/2022] Open
Abstract
Enterovirus 71 (EV71), a major causative agent of hand-foot-and-mouth disease (HFMD), causes outbreaks among children in the Asia-Pacific region. A vaccine is urgently needed. Based on successful pre-clinical work, phase I and II clinical trials of an inactivated EV71 vaccine, which included the participants of 288 and 660 respectively, have been conducted. In the present study, the immune response and the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) of 30 infants (6 to 11 months) immunized with this vaccine or placebo and consented to join this study in the phase II clinical trial were analyzed. The results showed significantly greater neutralizing antibody and specific T cell responses in vaccine group after two inoculations on days 0 and 28. Additionally, more than 600 functional genes that were up- or down-regulated in PBMCs were identified by the microarray assay, and these genes included 68 genes associated with the immune response in vaccine group. These results emphasize the gene expression profile of the immune system in response to an inactivated EV71 vaccine in humans and confirmed that such an immune response was generated as the result of the positive mobilization of the immune system. Furthermore, the immune response was not accompanied by the development of a remarkable inflammatory response. Clinical Trial Registration: NCT01391494 and NCT01512706.
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MESH Headings
- Animals
- Antibodies, Neutralizing/blood
- Antibodies, Neutralizing/immunology
- Antibodies, Viral/blood
- Antibodies, Viral/immunology
- Cytokines/blood
- Cytokines/genetics
- Cytokines/immunology
- Double-Blind Method
- Enterovirus/immunology
- Gene Expression Profiling
- Gene Expression Regulation/drug effects
- Gene Expression Regulation/immunology
- Hand, Foot and Mouth Disease/genetics
- Hand, Foot and Mouth Disease/immunology
- Hand, Foot and Mouth Disease/prevention & control
- Hand, Foot and Mouth Disease/virology
- Humans
- Immunity, Cellular/drug effects
- Infant
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Leukocytes, Mononuclear/virology
- Microarray Analysis
- Placebos
- Vaccination
- Vaccines, Inactivated
- Viral Vaccines/administration & dosage
- Viral Vaccines/immunology
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Affiliation(s)
- Longding Liu
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Ying Zhang
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Jingjing Wang
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Hongling Zhao
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Li Jiang
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Yanchun Che
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Haijin Shi
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Rongcheng Li
- Guangxi Province Centers for Disease Control and Prevention, Nanning, People’s Republic of China
| | - Zhaojun Mo
- Guangxi Province Centers for Disease Control and Prevention, Nanning, People’s Republic of China
| | - Teng Huang
- Guangxi Province Centers for Disease Control and Prevention, Nanning, People’s Republic of China
| | - Zhenglun Liang
- National Institutes for Food and Drug Control, Beijing, People’s Republic of China
| | - Qunying Mao
- National Institutes for Food and Drug Control, Beijing, People’s Republic of China
| | - Lichun Wang
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Chenghong Dong
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Yun Liao
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Lei Guo
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Erxia Yang
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Jing Pu
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Lei Yue
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Zhenxin Zhou
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
| | - Qihan Li
- Institute of Medical Biology, Chinese Academy of Medicine Science, Peking Union Medical College, Kunming, People’s Republic of China
- * E-mail:
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Tran B, Dancey JE, Kamel-Reid S, McPherson JD, Bedard PL, Brown AM, Zhang T, Shaw P, Onetto N, Stein L, Hudson TJ, Neel BG, Siu LL. Cancer Genomics: Technology, Discovery, and Translation. J Clin Oncol 2012; 30:647-60. [DOI: 10.1200/jco.2011.39.2316] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In recent years, the increasing awareness that somatic mutations and other genetic aberrations drive human malignancies has led us within reach of personalized cancer medicine (PCM). The implementation of PCM is based on the following premises: genetic aberrations exist in human malignancies; a subset of these aberrations drive oncogenesis and tumor biology; these aberrations are actionable (defined as having the potential to affect management recommendations based on diagnostic, prognostic, and/or predictive implications); and there are highly specific anticancer agents available that effectively modulate these targets. This article highlights the technology underlying cancer genomics and examines the early results of genome sequencing and the challenges met in the discovery of new genetic aberrations. Finally, drawing from experiences gained in a feasibility study of somatic mutation genotyping and targeted exome sequencing led by Princess Margaret Hospital–University Health Network and the Ontario Institute for Cancer Research, the processes, challenges, and issues involved in the translation of cancer genomics to the clinic are discussed.
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Affiliation(s)
- Ben Tran
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Janet E. Dancey
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Suzanne Kamel-Reid
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - John D. McPherson
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Philippe L. Bedard
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Andrew M.K. Brown
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Tong Zhang
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Patricia Shaw
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Nicole Onetto
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Lincoln Stein
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Thomas J. Hudson
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Benjamin G. Neel
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
| | - Lillian L. Siu
- Ben Tran, Philippe L. Bedard, and Lillian L. Siu, Princess Margaret Hospital, University Health Network, University of Toronto; Janet E. Dancey, John D. McPherson, Andrew M.K. Brown, Nicole Onetto, Lincoln Stein, and Thomas J. Hudson, Ontario Institute for Cancer Research; Suzanne Kamel-Reid, Tong Zhang, and Patricia Shaw, Toronto General Hospital, University Health Network, University of Toronto; John D. McPherson, Nicole Onetto, Lincoln Stein, Thomas J. Hudson, and Benjamin G. Neel, University of
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Kotlan B, Umansky V, Malyguine AM, Marincola FM, Shurin MR. Conference Scene: Immunotherapy reaches new milestones in cancer eradication. Immunotherapy 2012; 3:1131-7. [PMID: 21995567 DOI: 10.2217/imt.11.114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Biotherapy is widely considered as the fourth treatment modality for patients with cancer, and uses the constantly increasing knowledge in molecular biology, cell biology and immunology. Biotherapy uses naturally occurring biological molecules (e.g., cytokines and antibodies) or works by the manipulation of normal biological mechanisms (controlling or inhibiting tumor growth). Important achievements in anticancer drug development are immunotherapeutic strategies recently approved by the US FDA as well as clinical data of the cancer patients treated in clinical trials. There is a need to expand these novel cancer immunotherapeutic modalities for cancer patients all over the world. To meet that goal, it is essential to spread the information, to summarize the new clinical data and to draw the conclusions from the clinical and preclinical investigations. These frontline tasks can be well advanced by organizing international conferences in this domain in less scientifically developed countries, with a significant tumor burden statistics. Therefore, special efforts were done to organize the 2nd International Cancer Immunotherapy and Immunomonitoring Conference (CITIM-2011) in Hungary.
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Affiliation(s)
- Beatrix Kotlan
- Center of Surgical & Molecular Tumor pathology, Department of Molecular Immunology & Toxicology, National Institute of Oncology, 1122 Rath Gy Street 7-9, Budapest, Hungary.
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Komatsu N, Matsueda S, Tashiro K, Ioji T, Shichijo S, Noguchi M, Yamada A, Doi A, Suekane S, Moriya F, Matsuoka K, Kuhara S, Itoh K, Sasada T. Gene expression profiles in peripheral blood as a biomarker in cancer patients receiving peptide vaccination. Cancer 2011; 118:3208-21. [PMID: 22071976 DOI: 10.1002/cncr.26636] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Revised: 08/26/2011] [Accepted: 09/16/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Because only a subset of patients show clinical responses to peptide-based cancer vaccination, it is critical to identify biomarkers for selecting patients who would most likely benefit from this treatment. METHODS The authors characterized the gene expression profiles in peripheral blood of vaccinated patients to identify biomarkers to predict patient prognosis. Peripheral blood was obtained from advanced castration-resistant prostate cancer patients, who survived for >900 days (long-term survivors, n = 20) or died within 300 days (short-term survivors, n = 20) after treatment with personalized peptide vaccination. Gene expression profiles in prevaccination and postvaccination peripheral blood mononuclear cells (PBMCs) were assessed by DNA microarray. RESULTS There were no statistically significant differences in the clinical or pathological features between the 2 groups. Microarray analysis of prevaccination PBMCs identified 19 genes that were differentially expressed between the short-term and long-term survivors. Among the 15 up-regulated genes in the short-term survivors, 13 genes, which were also differentially expressed in postvaccination PBMCs, were associated with gene signatures of granulocytes. When a set of 4 differentially expressed genes were selected as the best combination to determine patient survival, prognosis was correctly predicted in 12 of 13 patients in a validation set (accuracy, 92%). CONCLUSIONS These results suggested that abnormal granulocytes present in the PBMC faction may contribute to poor prognosis in advanced prostate cancer patients receiving personalized peptide vaccination. Gene expression profiling in peripheral blood might thus be informative for devising better therapeutic strategies by predicting patient prognosis after cancer vaccines.
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Affiliation(s)
- Nobukazu Komatsu
- Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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Spivey TL, Uccellini L, Ascierto ML, Zoppoli G, De Giorgi V, Delogu LG, Engle AM, Thomas JM, Wang E, Marincola FM, Bedognetti D. Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis. J Transl Med 2011; 9:174. [PMID: 21992116 PMCID: PMC3213224 DOI: 10.1186/1479-5876-9-174] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Accepted: 10/12/2011] [Indexed: 02/06/2023] Open
Abstract
In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.
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Affiliation(s)
- Tara L Spivey
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA
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Review and cross-validation of gene expression signatures and melanoma prognosis. J Invest Dermatol 2011; 132:274-83. [PMID: 21956122 DOI: 10.1038/jid.2011.305] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In melanoma, there is an urgent need to identify novel biomarkers with prognostic performance superior to traditional clinical and histological parameters. Gene expression-based prognostic signatures offer promise, but studies have been challenged by sample scarcity, cohort heterogeneity, and doubts about the efficacy of such signatures relative to current clinical practices. Motivated by new studies that have begun to address these challenges, we reviewed prognostic signatures derived from gene expression microarray analysis of human melanoma tissue. We used REMARK-based criteria to select the most relevant studies and directly compared their signature gene lists. Through functional ontology enrichment analysis, we observed that these independent data sets converge in part upon immune response processes and the G-protein signaling NRAS-regulation pathway, both important in melanoma development and progression. The signatures correctly predicted patient outcome in independent gene expression data sets with some notably low misclassification rates, particularly among studies involving more advanced-stage tumors. This successful cross-validation indicates that gene expression analysis-based signatures are becoming translationally relevant to care of melanoma patients, as well as improving understanding of the aspects of melanoma biology that determine patient outcome.
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Ascierto ML, Giorgi VD, Liu Q, Bedognetti D, Spivey TL, Murtas D, Uccellini L, Ayotte BD, Stroncek DF, Chouchane L, Manjili MH, Wang E, Marincola FM. An immunologic portrait of cancer. J Transl Med 2011; 9:146. [PMID: 21875439 PMCID: PMC3175185 DOI: 10.1186/1479-5876-9-146] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 08/29/2011] [Indexed: 12/31/2022] Open
Abstract
The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior.
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Affiliation(s)
- Maria Libera Ascierto
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
- Department of Internal Medicine, University of Genoa, Italy
- Center of Excellence for Biomedical Research (CEBR), Genoa, Italy
| | - Valeria De Giorgi
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Qiuzhen Liu
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Davide Bedognetti
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
- Center of Excellence for Biomedical Research (CEBR), Genoa, Italy
- Department of Oncology, Biology and Genetics and National Cancer Research Institute of Genoa, Italy
| | - Tara L Spivey
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Daniela Murtas
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Lorenzo Uccellini
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Ben D Ayotte
- Department of Biology, Northern Michigan University, Marquette, MI 49855,USA
| | - David F Stroncek
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Lotfi Chouchane
- Weill Cornell Medical College in Qatar, Education City, Doha Qatar Box 24144
| | - Masoud H Manjili
- Department of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center, Richmond, VA 23298, USA
| | - Ena Wang
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Francesco M Marincola
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland, 20892, USA
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Clancy T, Pedicini M, Castiglione F, Santoni D, Nygaard V, Lavelle TJ, Benson M, Hovig E. Immunological network signatures of cancer progression and survival. BMC Med Genomics 2011; 4:28. [PMID: 21453479 PMCID: PMC3094196 DOI: 10.1186/1755-8794-4-28] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2010] [Accepted: 03/31/2011] [Indexed: 12/13/2022] Open
Abstract
Background The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. Methods To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. Results The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. Conclusions The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides.
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Affiliation(s)
- Trevor Clancy
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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Kotlan B, Balwit JM. Pioneering the trail of cancer immunotherapy. Expert Rev Anticancer Ther 2011; 11:351-4. [PMID: 21417850 DOI: 10.1586/era.10.229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The annual conference of the International Society for Biological Therapy of Cancer (iSBTc), recently renamed the Society for Immunotherapy of Cancer (SITC), provides clinicians and scientists with a uniquely broad yet focused view of the growing field of tumor immunology and cancer immunotherapy. In this time of exciting new developments in cancer immunotherapy, it is critically important to effectively guide new immune-based advances from bench to bedside to improve outcomes of patients with cancer. iSBTc/SITC with its dedicated leadership (past and present) provides this guidance through its Annual Meeting and associated programs. This year the society celebrated its 25th Anniversary in Hyatt Regency Washington on Capitol Hill (Washington DC, USA), with educational offerings from 30 September to 4 October 2010.
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Affiliation(s)
- Beatrix Kotlan
- Center of Surgical and Molecular Tumor Pathology, National Institute of Oncology, Budapest, 1122 Rath Gy Street 7-9, Hungary.
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