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Jin X, Han H, Liang Q. Effects of surgical trauma and intraoperative blood loss on tumour progression. Front Oncol 2024; 14:1412367. [PMID: 38912060 PMCID: PMC11190163 DOI: 10.3389/fonc.2024.1412367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 05/22/2024] [Indexed: 06/25/2024] Open
Abstract
Surgery is the primary treatment of choice for tumours, and improves prognosis, prolongs survival and is potentially curative. Previous studies have described the effects of anaesthesia and changes in the neuroendocrine, circulatory and sympathetic nervous systems on postoperative cancer progression. There is growing evidence that intraoperative blood loss is an independent prognostic factor for tumour recurrence, postoperative inflammation is a predictor of cancer prognosis, and immunosuppressive status correlates with the degree of surgical damage. This paper outlines the potential mechanisms by which blood loss, surgical trauma and postoperative immunosuppressive status contribute to tumour growth and recurrence by reducing intraoperative haemorrhage and perioperative immunotherapy, thereby reducing tumour growth and recurrence, and improving long-term prognosis.
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Affiliation(s)
| | | | - Qilian Liang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Grauers Wiktorin H, Aydin E, Kiffin R, Vilhav C, Bourghardt Fagman J, Kaya M, Paul S, Westman B, Bratlie SO, Naredi P, Hellstrand K, Martner A. Impact of Surgery-Induced Myeloid-derived Suppressor Cells and the NOX2/ROS Axis on Postoperative Survival in Human Pancreatic Cancer. CANCER RESEARCH COMMUNICATIONS 2024; 4:1135-1149. [PMID: 38598844 PMCID: PMC11044860 DOI: 10.1158/2767-9764.crc-23-0447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/12/2024]
Abstract
Preclinical studies imply that surgery triggers inflammation that may entail tumor outgrowth and metastasis. The potential impact of surgery-induced inflammation in human pancreatic cancer is insufficiently explored. This study included 17 patients with periampullary cancer [pancreatic ductal adenocarcinoma (PDAC) n = 14, ampullary carcinoma n = 2, cholangiocarcinoma n = 1] undergoing major pancreatic cancer surgery with curative intent. We analyzed the potential impact of preoperative and postoperative immune phenotypes and function on postoperative survival with >30 months follow-up. The surgery entailed prompt expansion of monocytic myeloid-derived suppressor cells (M-MDSC) that generated NOX2-derived reactive oxygen species (ROS). Strong induction of immunosuppressive M-MDSC after surgery predicted poor postoperative survival and coincided with reduced functionality of circulating natural killer (NK) cells. The negative impact of surgery-induced M-MDSC on survival remained significant in separate analysis of patients with PDAC. M-MDSC-like cells isolated from patients after surgery significantly suppressed NK cell function ex vivo, which was reversed by inhibition of NOX2-derived ROS. High NOX2 subunit expression within resected tumors from patients with PDAC correlated with poor survival whereas high expression of markers of cytotoxic cells associated with longer survival. The surgery-induced myeloid inflammation was recapitulated in vivo in a murine model of NK cell-dependent metastasis. Surgical stress thus induced systemic accumulation of M-MDSC-like cells and promoted metastasis of NK cell-sensitive tumor cells. Genetic or pharmacologic suppression of NOX2 reduced surgery-induced inflammation and distant metastasis in this model. We propose that NOX2-derived ROS generated by surgery-induced M-MDSC may be targeted for improved outcome after pancreatic cancer surgery. SIGNIFICANCE Pancreatic cancer surgery triggered pronounced accumulation of NOX2+ myeloid-derived suppressor cells that inhibited NK cell function and negatively prognosticated postoperative patient survival. We propose the targeting of M-MDSC as a conceivable strategy to reduce postoperative immunosuppression in pancreatic cancer.
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Affiliation(s)
- Hanna Grauers Wiktorin
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ebru Aydin
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Roberta Kiffin
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Caroline Vilhav
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Johan Bourghardt Fagman
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mustafa Kaya
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sanchari Paul
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Beatrice Westman
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Svein Olav Bratlie
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Peter Naredi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Martner
- TIMM Laboratory, Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Wu J, Chan YT, Lu Y, Wang N, Feng Y. The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma. Med Res Rev 2023; 43:1946-1973. [PMID: 37102365 DOI: 10.1002/med.21967] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/23/2023] [Accepted: 04/13/2023] [Indexed: 04/28/2023]
Abstract
Surgery remains to be the mainstay of treatment for hepatocellular carcinoma (HCC). Nonetheless, its therapeutic efficacy is significantly impaired by postoperative recurrence, which occurs in more than half of cases as a result of intrahepatic metastasis or de novo tumorigenesis. For decades, most therapeutic strategies on inhibiting postoperative HCC recurrence have been focused on the residual tumor cells but satisfying therapeutic outcomes are barely observed in the clinic. In recent years, a better understanding of tumor biology allows us to shift our focus from tumor cells toward the postoperative tumor microenvironment (TME), which is gradually identified to play a pivotal role in tumor recurrence. In this review, we describe various surgical stress and surgical perturbation on postoperative TME. Besides, we discuss how such alternations in TME give rise to postoperative recurrence of HCC. Based on its clinical significance, we additionally highlight the potential of the postoperative TME as a target for postoperative adjuvant therapeutics.
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Affiliation(s)
- Junyu Wu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yau-Tuen Chan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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He ZN, Zhang CY, Zhao YW, He SL, Li Y, Shi BL, Hu JQ, Qi RZ, Hua BJ. Regulation of T cells by myeloid-derived suppressor cells: emerging immunosuppressor in lung cancer. Discov Oncol 2023; 14:185. [PMID: 37857728 PMCID: PMC10587041 DOI: 10.1007/s12672-023-00793-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs), major components maintaining the immune suppressive microenvironment in lung cancer, are relevant to the invasion, metastasis, and poor prognosis of lung cancer, through the regulation of epithelial-mesenchymal transition, remodeling of the immune microenvironment, and regulation of angiogenesis. MDSCs regulate T-cell immune functions by maintaining a strong immunosuppressive microenvironment and promoting tumor invasion. This raises the question of whether reversing the immunosuppressive effect of MDSCs on T cells can improve lung cancer treatment. To understand this further, this review explores the interactions and specific mechanisms of different MDSCs subsets, including regulatory T cells, T helper cells, CD8 + T cells, natural killer T cells, and exhausted T cells, as part of the lung cancer immune microenvironment. Second, it focuses on the guiding significance confirmed via clinical liquid biopsy and tissue biopsy that different MDSC subsets improve the prognosis of lung cancer. Finally, we conclude that targeting MDSCs through action targets or signaling pathways can help regulate T-cell immune functions and suppress T-cell exhaustion. In addition, immune checkpoint inhibitors targeting MDSCs may serve as a new approach for enhancing the efficiency of immunotherapy and targeted therapy for lung cancer in the future, providing better comprehensive options for lung cancer treatment.
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Affiliation(s)
- Zhong-Ning He
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | | | - Yu-Wei Zhao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shu-Lin He
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Shanxi Medical University, Shanxi, China
| | - Yue Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Shanxi Medical University, Shanxi, China
| | - Bo-Lun Shi
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jia-Qi Hu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Shanxi Medical University, Shanxi, China
| | - Run-Zhi Qi
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Bao-Jin Hua
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Does Primary Tumor Resection Induce Accelerated Metastasis in Breast Cancer? A Review. J Surg Res 2023; 283:1005-1017. [PMID: 36914990 DOI: 10.1016/j.jss.2022.11.064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 11/19/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Over a century of cumulative experimental results and clinical data have suggested that surgical procedures of primary tumors promote tumor progression and metastasis in breast cancer and other cancer patients, suggesting a potential interplay linking primary tumors and distant lesions that lead to metastasis development triggered by primary tumor removal. Such evidence may generate a departure in terms of our attitude toward the surgery. However, the reliability and prognostic benefits of tumor surgery, especially for chemotherapy-resistant patients, are indisputable. Thus, it is important to explore the mechanism underlying this surgery-induced cancer progression to guide individual clinical treatment and improve tumor control. MATERIALS AND METHODS We conducted a comprehensive review in PubMed in October 2021 to determine the article outline. Non-English and repetitive articles were excluded. The year, topic, key findings, and opinions of each article were gathered. RESULTS This review not only comprehensively summarizes the potential mechanisms of primary tumors interacting with the growth of metastases but also discusses whether and how surgical resection of primary lesions can trigger tumor metastasis and development. At the same time, this article also provides our understanding of clinical findings and future directions on this topic. In addition, the combination of surgery and some potentially beneficial therapeutic interventions for postoperative tumor metastasis control was also mentioned. CONCLUSIONS There are viewpoints supporting an acceleration of metastasis after surgery for breast cancer and fundamental research on relevant therapies, although controversial. Further attention should be focused on the gap between current preclinical data and the complicated clinical therapeutic combination during surgery in metastatic breast cancer patients.
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Immunophenotype and function of circulating myeloid derived suppressor cells in COVID-19 patients. Sci Rep 2022; 12:22570. [PMID: 36581679 PMCID: PMC9799710 DOI: 10.1038/s41598-022-26943-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
The pathogenesis of coronavirus disease 2019 (COVID-19) is not fully elucidated. COVID-19 is due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes severe illness and death in some people by causing immune dysregulation and blood T cell depletion. Increased numbers of myeloid-derived suppressor cells (MDSCs) play a diverse role in the pathogenesis of many infections and cancers but their function in COVID-19 remains unclear. To evaluate the function of MDSCs in relation with the severity of COVID-19. 26 PCR-confirmed COVID-19 patients including 12 moderate and 14 severe patients along with 11 healthy age- and sex-matched controls were enrolled. 10 ml whole blood was harvested for cell isolation, immunophenotyping and stimulation. The immunophenotype of MDSCs by flow cytometry and T cells proliferation in the presence of MDSCs was evaluated. Serum TGF-β was assessed by ELISA. High percentages of M-MDSCs in males and of P-MDSCs in female patients were found in severe and moderate affected patients. Isolated MDSCs of COVID-19 patients suppressed the proliferation and intracellular levels of IFN-γ in T cells despite significant suppression of T regulatory cells but up-regulation of precursor regulatory T cells. Serum analysis shows increased levels of TGF-β in severe patients compared to moderate and control subjects (HC) (P = 0.003, P < 0.0001, respectively). The frequency of MDSCs in blood shows higher frequency among both moderate and severe patients and may be considered as a predictive factor for disease severity. MDSCs may suppress T cell proliferation by releasing TGF-β.
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Viscardi G, Vitiello F, Servetto A, Gristina V, Pizzutilo EG, Canciello MA, Medusa PM, Salomone F, Di Guida G, Mollica M, Aronne L, Scaramuzzi R, Napolitano F, Battiloro C, Caputo F, Gilli M, Totaro G, Curcio C, Rocco D, Montesarchio V. Moving Immune Checkpoint Inhibitors to Early Non-Small Cell Lung Cancer: A Narrative Review. Cancers (Basel) 2022; 14:cancers14235810. [PMID: 36497292 PMCID: PMC9735901 DOI: 10.3390/cancers14235810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/17/2022] [Accepted: 11/17/2022] [Indexed: 11/29/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Since prognosis of early-stage non-small cell lung cancer (NSCLC) remains dismal for common relapses after curative surgery, considerable efforts are currently focused on bringing immunotherapy into neoadjuvant and adjuvant settings. Previously, perioperative chemotherapy showed only a modest but significative improvement in overall survival. The presence of broad tumor neoantigens load at primary tumor prior to surgery as well as the known immunosuppressive status following resection represent the main rationale for immunotherapy in early disease. Several trials have been conducted in recent years, leading to atezolizumab and nivolumab approval in the adjuvant and neoadjuvant setting, respectively, and perioperative immunotherapy in NSCLC remains a field of active clinical and preclinical investigation. Unanswered questions in perioperative therapy in NSCLC include the optimal sequence and timing of chemotherapy and immunotherapy, the potential of combination strategies, the role of predictive biomarkers for patient selection and the choice of useful endpoints in clinical investigation.
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Affiliation(s)
- Giuseppe Viscardi
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
- Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Via Sergio Pansini 5, 80131 Naples, Italy
- Correspondence:
| | - Fabiana Vitiello
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alberto Servetto
- Medical Oncology, Department of Clinical Medicine and Surgery, Università degli Studi di Napoli “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Valerio Gristina
- Medical Oncology, Department of Surgical, Oncological and Oral Sciences, Università degli Studi di Palermo, Via Liborio Giuffrè 5, 90127 Palermo, Italy
| | - Elio Gregory Pizzutilo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza dell’Ospedale Maggiore 3, 20162 Milan, Italy
- Departmento of Oncology and Hematology, Università degli Studi di Milano, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Maria Anna Canciello
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
- Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Paola Maria Medusa
- Pneumology Unit, Università degli Studi della Campania “Luigi Vanvitelli”, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Fabio Salomone
- Medical Oncology, Department of Clinical Medicine and Surgery, Università degli Studi di Napoli “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Gaetano Di Guida
- Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Mariano Mollica
- Respiratory Pathophysiology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Luigi Aronne
- Pneumology Unit, Università degli Studi della Campania “Luigi Vanvitelli”, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Roberto Scaramuzzi
- Thoracic Surgery, Department of General and Specialistic Surgery, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Filomena Napolitano
- Thoracic Surgery, Department of General and Specialistic Surgery, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Ciro Battiloro
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Francesca Caputo
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Marina Gilli
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Giuseppe Totaro
- Radiotherapy Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola, 80131 Naples, Italy
| | - Carlo Curcio
- Thoracic Surgery, Department of General and Specialistic Surgery, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Danilo Rocco
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Vincenzo Montesarchio
- Medical Oncology, Department of Pneumology and Oncology, AORN Ospedali dei Colli, Via Leonardo Bianchi, 80131 Naples, Italy
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Preventing Surgery-Induced NK Cell Dysfunction Using Anti-TGF-β Immunotherapeutics. Int J Mol Sci 2022; 23:ijms232314608. [PMID: 36498937 PMCID: PMC9737532 DOI: 10.3390/ijms232314608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/11/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Natural Killer (NK) cell cytotoxicity and interferon-gamma (IFNγ) production are profoundly suppressed postoperatively. This dysfunction is associated with increased morbidity and cancer recurrence. NK activity depends on the integration of activating and inhibitory signals, which may be modulated by transforming growth factor-beta (TGF-β). We hypothesized that impaired postoperative NK cell IFNγ production is due to altered signaling pathways caused by postoperative TGF-β. NK cell receptor expression, downstream phosphorylated targets, and IFNγ production were assessed using peripheral blood mononuclear cells (PBMCs) from patients undergoing cancer surgery. Healthy NK cells were incubated in the presence of healthy/baseline/postoperative day (POD) 1 plasma and in the presence/absence of a TGF-β-blocking monoclonal antibody (mAb) or the small molecule inhibitor (smi) SB525334. Single-cell RNA sequencing (scRNA-seq) was performed on PBMCs from six patients with colorectal cancer having surgery at baseline/on POD1. Intracellular IFNγ, activating receptors (CD132, CD212, NKG2D, DNAM-1), and downstream target (STAT5, STAT4, p38 MAPK, S6) phosphorylation were significantly reduced on POD1. Furthermore, this dysfunction was phenocopied in healthy NK cells through incubation with rTGF-β1 or POD1 plasma and was prevented by the addition of anti-TGF-β immunotherapeutics (anti-TGF-β mAb or TGF-βR smi). Targeted gene analysis revealed significant decreases in S6 and FKBP12, an increase in Shp-2, and a reduction in NK metabolism-associated transcripts on POD1. pSmad2/3 was increased and pS6 was reduced in response to rTGF-β1 on POD1, changes that were prevented by anti-TGF-β immunotherapeutics. Together, these results suggest that both canonical and mTOR pathways downstream of TGF-β mediate phenotypic changes that result in postoperative NK cell dysfunction.
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Cheng X, Zhang H, Hamad A, Huang H, Tsung A. Surgery-mediated tumor-promoting effects on the immune microenvironment. Semin Cancer Biol 2022; 86:408-419. [PMID: 35066156 PMCID: PMC11770836 DOI: 10.1016/j.semcancer.2022.01.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 02/07/2023]
Abstract
Surgical resection continues to be the mainstay treatment for solid cancers even though chemotherapy and immunotherapy have significantly improved patient overall survival and progression-free survival. Numerous studies have shown that surgery induces the dissemination of circulating tumor cells (CTCs) and that the resultant inflammatory response promotes occult tumor growth and the metastatic process by forming a supportive tumor microenvironment (TME). Surgery-induced platelet activation is one of the initial responses to a wound and the formation of fibrin clots can provide the scaffold for recruited inflammatory cells. Activated platelets can also shield CTCs to protect them from blood shear forces and promote CTCs evasion of immune destruction. Similarly, neutrophils are recruited to the fibrin clot and enhance cancer metastatic dissemination and progression by forming neutrophil extracellular traps (NETs). Activated macrophages are also recruited to surgical sites to facilitate the metastatic spread. More importantly, the body's response to surgical insult results in the recruitment and expansion of immunosuppressive cell populations (i.e. myeloid-derived suppressor cells and regulatory T cells) and in the suppression of natural killer (NK) cells that contribute to postoperative cancer recurrence and metastasis. In this review, we seek to provide an overview of the pro-tumorigenic mechanisms resulting from surgery's impact on these cells in the TME. Further understanding of these events will allow for the development of perioperative therapeutic strategies to prevent surgery-associated metastasis.
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Affiliation(s)
- Xiang Cheng
- Division of Surgical Oncology, Department of Surgery, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Hongji Zhang
- Division of Surgical Oncology, Department of Surgery, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Ahmad Hamad
- Division of Surgical Oncology, Department of Surgery, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Hai Huang
- Division of Surgical Oncology, Department of Surgery, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Allan Tsung
- Division of Surgical Oncology, Department of Surgery, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA.
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10
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Patysheva M, Frolova A, Larionova I, Afanas'ev S, Tarasova A, Cherdyntseva N, Kzhyshkowska J. Monocyte programming by cancer therapy. Front Immunol 2022; 13:994319. [PMID: 36341366 PMCID: PMC9631446 DOI: 10.3389/fimmu.2022.994319] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/27/2022] [Indexed: 08/27/2023] Open
Abstract
Monocytes in peripheral blood circulation are the precursor of essential cells that control tumor progression, that include tumor-associated macrophages (TAMs), dendritic cells (DCs) and myeloid-derive suppressor cells (MDSC). Monocytes-derived cells orchestrate immune reactions in tumor microenvironment that control disease outcome and efficiency of cancer therapy. Four major types of anti-cancer therapy, surgery, radiotherapy, chemotherapy, and most recent immunotherapy, affect tumor-associated macrophage (TAM) polarization and functions. TAMs can also decrease the efficiency of therapy in a tumor-specific way. Monocytes is a major source of TAMs, and are recruited to tumor mass from the blood circulation. However, the mechanisms of monocyte programming in circulation by different therapeutic onsets are only emerging. In our review, we present the state-of-the art about the effects of anti-cancer therapy on monocyte progenitors and their dedifferentiation, on the content of monocyte subpopulations and their transcriptional programs in the circulation, on their recruitment into tumor mass and their potential to give origin for TAMs in tumor-specific microenvironment. We have also summarized very limited available knowledge about genetics that can affect monocyte interaction with cancer therapy, and highlighted the perspectives for the therapeutic targeting of circulating monocytes in cancer patients. We summarized the knowledge about the mediators that affect monocytes fate in all four types of therapies, and we highlighted the perspectives for targeting monocytes to develop combined and minimally invasive anti-cancer therapeutic approaches.
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Affiliation(s)
- Marina Patysheva
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Laboratory of Tumor Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Anastasia Frolova
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Laboratory of Tumor Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
- Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia
| | - Sergey Afanas'ev
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Department of Abdominal Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Anna Tarasova
- Department of Abdominal Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Nadezhda Cherdyntseva
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
- Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg – Hessen, Mannheim, Germany
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11
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Market M, Tennakoon G, Auer RC. Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. Int J Mol Sci 2021; 22:ijms222111378. [PMID: 34768810 PMCID: PMC8583911 DOI: 10.3390/ijms222111378] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022] Open
Abstract
Surgical resection is the foundation for the curative treatment of solid tumors. However, metastatic recurrence due to the difficulty in eradicating micrometastases remain a feared outcome. Paradoxically, despite the beneficial effects of surgical removal of the primary tumor, the physiological stress resulting from surgical trauma serves to promote cancer recurrence and metastasis. The postoperative environment suppresses critical anti-tumor immune effector cells, including Natural Killer (NK) cells. The literature suggests that NK cells are critical mediators in the formation of metastases immediately following surgery. The following review will highlight the mechanisms that promote the formation of micrometastases by directly or indirectly inducing NK cell suppression following surgery. These include tissue hypoxia, neuroendocrine activation, hypercoagulation, the pro-inflammatory phase, and the anti-inflammatory phase. Perioperative therapeutic strategies designed to prevent or reverse NK cell dysfunction will also be examined for their potential to improve cancer outcomes by preventing surgery-induced metastases.
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Affiliation(s)
- Marisa Market
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 8M5, Canada; (M.M.); (G.T.)
- The Ottawa Hospital Research Institute, Ottawa, ON K1G 4E3, Canada
| | - Gayashan Tennakoon
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 8M5, Canada; (M.M.); (G.T.)
| | - Rebecca C. Auer
- The Ottawa Hospital Research Institute, Ottawa, ON K1G 4E3, Canada
- Department of General Surgery, The Ottawa Hospital, Ottawa, ON K1Y 4E9, Canada
- Correspondence: ; Tel.: +1-613-722-7000
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12
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Gillot L, Baudin L, Rouaud L, Kridelka F, Noël A. The pre-metastatic niche in lymph nodes: formation and characteristics. Cell Mol Life Sci 2021; 78:5987-6002. [PMID: 34241649 PMCID: PMC8316194 DOI: 10.1007/s00018-021-03873-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 05/10/2021] [Accepted: 06/05/2021] [Indexed: 02/06/2023]
Abstract
Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.
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Affiliation(s)
- Lionel Gillot
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
| | - Louis Baudin
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
| | - Loïc Rouaud
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
| | - Frédéric Kridelka
- Department of Obstetrics and Gynecology, CHU of Liege, 4000 Liege, Belgium
| | - Agnès Noël
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
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13
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Tang F, Tie Y, Hong W, Wei Y, Tu C, Wei X. Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection. Ann Surg Oncol 2021; 28:4030-4048. [PMID: 33258011 PMCID: PMC7703739 DOI: 10.1245/s10434-020-09371-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/29/2020] [Indexed: 02/05/2023]
Abstract
Surgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a "fertile soil" following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.
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Affiliation(s)
- Fan Tang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yan Tie
- Department of Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Weiqi Hong
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Chongqi Tu
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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14
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Zhang Y, Wang X, Zhang R, Wang X, Fu H, Yang W. MDSCs interactions with other immune cells and their role in maternal-fetal tolerance. Int Rev Immunol 2021; 41:534-551. [PMID: 34128752 DOI: 10.1080/08830185.2021.1938566] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
MDSCs (myeloid-derived suppressor cells) are a population of immature and heterogeneous bone marrow cells with immunosuppressive functions, and they are mainly divided into two subgroups: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Immunosuppression is the main and most important function of MDSCs, and they mainly exert an inhibitory effect through endoplasmic reticulum stress and some enzymes related to inhibitors, as well as some cytokines and other factors. In addition, MDSCs also interact with other immune cells, especially NK cells, DCs and Tregs, to participate in immune regulation. A large number of MDSCs are found during normal pregnancy. Combined with their immunosuppressive effects, these results suggest that MDSCs are likely to be closely related to maternal-fetal immune tolerance. This review mainly shows the interaction of MDSCs with other immune cells and the important role of MDSCs in maternal-fetal tolerance. The current research shows that MDSCs are mainly mediated by STAT3, HLA-G, CXCR2, Arg-1 and HIF1-α in immune regulation during pregnancy. Interpreting maternal-fetal tolerance from the perspective of MDSCs provides a special perspective for research on immune regulation and maternal-fetal tolerance of MDSCs to obtain a more comprehensive understanding of immune regulation and immune tolerance.
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Affiliation(s)
- Yi Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaoya Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Rongchao Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xi Wang
- Department of Clinical Laboratory, The first Hospital of Jilin University, Changchun, China
| | - Haiying Fu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
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15
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Mandula JK, Rodriguez PC. Tumor-related stress regulates functional plasticity of MDSCs. Cell Immunol 2021; 363:104312. [PMID: 33652258 PMCID: PMC8026602 DOI: 10.1016/j.cellimm.2021.104312] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/15/2021] [Accepted: 01/29/2021] [Indexed: 12/15/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) impair protective anti-tumor immunity and remain major obstacles that stymie the effectiveness of promising cancer therapies. Diverse tumor-derived stressors galvanize the differentiation, intra-tumoral expansion, and immunomodulatory function of MDSCs. These tumor-associated 'axes of stress' underwrite the immunosuppressive programming of MDSCs in cancer and contribute to the phenotypic/functional heterogeneity that characterize tumor-MDSCs. This review discusses various tumor-associated axes of stress that direct MDSC development, accumulation, and immunosuppressive function, as well as current strategies aimed at overcoming the detrimental impact of MDSCs in cancer. To better understand the constellation of signals directing MDSC biology, we herein summarize the pivotal roles, signaling mediators, and effects of reactive oxygen/nitrogen species-related stress, chronic inflammatory stress, hypoxia-linked stress, endoplasmic reticulum stress, metabolic stress, and therapy-associated stress on MDSCs. Although therapeutic targeting of these processes remains mostly pre-clinical, intercepting signaling through the axes of stress could overcome MDSC-related immune suppression in tumor-bearing hosts.
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Affiliation(s)
- Jessica K Mandula
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Paulo C Rodriguez
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
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16
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Neuroimmune Regulation of Surgery-Associated Metastases. Cells 2021; 10:cells10020454. [PMID: 33672617 PMCID: PMC7924204 DOI: 10.3390/cells10020454] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/12/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro–immuno–oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision.
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17
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Explicating the Pivotal Pathogenic, Diagnostic, and Therapeutic Biomarker Potentials of Myeloid-Derived Suppressor Cells in Glioblastoma. DISEASE MARKERS 2020; 2020:8844313. [PMID: 33204365 PMCID: PMC7657691 DOI: 10.1155/2020/8844313] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/19/2020] [Accepted: 10/24/2020] [Indexed: 11/17/2022]
Abstract
Glioblastoma (GBM) is a malignant and aggressive central nervous tumor that originates from astrocytes. These pathogenic astrocytes divide rapidly and are sustained by enormous network of blood vessels via which they receive requisite nutrients. It well proven that GBM microenvironment is extremely infiltrated by myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous cluster of immature myeloid progenitors. They are key mediates in immune suppression as well as sustenance glioma growth, invasion, vascularization, and upsurge of regulatory T cells via different molecules. MDSCs are often elevated in the peripheral blood of patients with GBM. MDSCs in the peripheral blood as well as those infiltrating the GBM microenvironment correlated with poor prognosis. Also, an upsurge in circulating MDSCs in the peripheral blood of patients with GBM was observed compared to benign and grade I/II glioma patients. GBM patients with good prognosis presented with reduced MDSCs as well as augmented dendritic cells. Almost all chemotherapeutic medication for GBM has shown no obvious improvement in overall survival in patients. Nevertheless, low-dose chemotherapies were capable of suppressing the levels of MDSCs in GBM as well as multiple tumor models with metastatic to the brain. Thus, MDSCs are potential diagnostic as well as therapeutic biomarkers for GBM patients.
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18
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Kiss M, Caro AA, Raes G, Laoui D. Systemic Reprogramming of Monocytes in Cancer. Front Oncol 2020; 10:1399. [PMID: 33042791 PMCID: PMC7528630 DOI: 10.3389/fonc.2020.01399] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 07/02/2020] [Indexed: 01/09/2023] Open
Abstract
Monocytes influence multiple aspects of tumor progression, including antitumor immunity, angiogenesis, and metastasis, primarily by infiltrating tumors, and differentiating into tumor-associated macrophages. Emerging evidence suggests that the tumor-induced systemic environment influences the development and phenotype of monocytes before their arrival to the tumor site. As a result, circulating monocytes show functional alterations in cancer, such as the acquisition of immunosuppressive activity and reduced responsiveness to inflammatory stimuli. In this review, we summarize available evidence about cancer-induced changes in monopoiesis and its impact on the abundance and function of monocytes in the periphery. In addition, we describe the phenotypical alterations observed in tumor-educated peripheral blood monocytes and highlight crucial gaps in our knowledge about additional cellular functions that may be affected based on transcriptomic studies. We also highlight emerging therapeutic strategies that aim to reverse cancer-induced changes in monopoiesis and peripheral monocytes to inhibit tumor progression and improve therapy responses. Overall, we suggest that an in-depth understanding of systemic monocyte reprogramming will have implications for cancer immunotherapy and the development of clinical biomarkers.
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Affiliation(s)
- Máté Kiss
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Aarushi Audhut Caro
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Geert Raes
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Damya Laoui
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
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19
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Ma Z, Zhen Y, Hu C, Yi H. Myeloid-Derived Suppressor Cell-Derived Arginase-1 Oppositely Modulates IL-17A and IL-17F Through the ESR/STAT3 Pathway During Colitis in Mice. Front Immunol 2020; 11:687. [PMID: 32391010 PMCID: PMC7188946 DOI: 10.3389/fimmu.2020.00687] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 03/26/2020] [Indexed: 12/19/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) play a crucial role in regulating the intestinal immune response during colitis. We previously revealed an essential role of MDSC in promoting TH17 cell polarization, which was found to be arginase-1 (Arg-1)-dependent; however, the underlying mechanism remains obscure. Here we report that percentage of MDSC decreased in ArgmyeKO mice during DSS-induced colitis. IL-17A levels reduced but IL-17F levels increased significantly in the colorectum of ArgmyeKO mice, leading to severe tissue damage and high risk of mortality rate. Activation of estrogen receptor (ESR) increased pSTAT3 level in MDSC and consequently led to elevated percentage of MDSC and more Arg-1 and inducible nitric oxide synthase expression in MDSC. Increased level of IL-17A and reduced level of IL-17F alleviated colitis in mice consequently. Together, these findings demonstrate a protective role of MDSC-derived Arg-1 during colitis after activates ESR/STAT3 signaling in MDSC. High level of Arg-1 favors accumulation of IL-17A, but reduced IL-17F expression in the colorectum of mice and ultimately leading to relief of colitis, indicating a potential clinical impact of MDSC-derived Arg-1 for controlling inflammatory bowel disease.
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Affiliation(s)
- Zhanchuan Ma
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China
| | - Yu Zhen
- Department of Dermatology, The First Hospital of Jilin University, Changchun, China
| | - Cong Hu
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China
| | - Huanfa Yi
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China
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20
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Kunimasa K, Goto T. Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges. Int J Mol Sci 2020; 21:E597. [PMID: 31963413 PMCID: PMC7014343 DOI: 10.3390/ijms21020597] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 02/08/2023] Open
Abstract
The immune system plays a dual role in tumor evolution-it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.
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Affiliation(s)
- Kei Kunimasa
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka 541-8567, Japan;
- Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan
| | - Taichiro Goto
- Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan
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21
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Peereboom DM, Alban TJ, Grabowski MM, Alvarado AG, Otvos B, Bayik D, Roversi G, McGraw M, Huang P, Mohammadi AM, Kornblum HI, Radivoyevitch T, Ahluwalia MS, Vogelbaum MA, Lathia JD. Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells. JCI Insight 2019; 4:130748. [PMID: 31600167 DOI: 10.1172/jci.insight.130748] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUNDMyeloid-derived suppressor cells (MDSCs) are elevated in the circulation of patients with glioblastoma (GBM), present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated.METHODSA phase 0/I dose-escalation clinical trial was conducted in patients with recurrent GBM treated 5-7 days before surgery with low-dose chemotherapy via capecitabine, followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multiparameter flow cytometry, and tumor tissue immune profiles were assessed via time-of-flight mass cytometry.RESULTSEleven patients total were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid. No serious adverse events related to the drug combination were observed. Compared with pretreatment baseline, circulating MDSCs were found to be higher after surgery in the 150-mg treatment arm and lower in the 300-mg and 450-mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared with untreated GBM patients in the 300-mg and 450-mg treatment arms.CONCLUSIONSLow-dose, metronomic capecitabine in combination with bevacizumab was well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.TRIAL REGISTRATIONClinicalTrials.gov NCT02669173.FUNDINGThis research was funded by the Cleveland Clinic, Case Comprehensive Cancer Center, the Musella Foundation, B*CURED, the NIH, the National Cancer Institute, the Sontag Foundation, Blast GBM, the James B. Pendleton Charitable Trust, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Capecitabine was provided in kind by Mylan Pharmaceuticals.
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Affiliation(s)
- David M Peereboom
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Tyler J Alban
- Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Matthew M Grabowski
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Alvaro G Alvarado
- Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA
| | - Balint Otvos
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Defne Bayik
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.,Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Gustavo Roversi
- Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mary McGraw
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Pengjing Huang
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Alireza M Mohammadi
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Harley I Kornblum
- Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA
| | - Tomas Radivoyevitch
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Manmeet S Ahluwalia
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| | | | - Justin D Lathia
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.,Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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22
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Niavarani SR, Lawson C, Bakos O, Boudaud M, Batenchuk C, Rouleau S, Tai LH. Lipid accumulation impairs natural killer cell cytotoxicity and tumor control in the postoperative period. BMC Cancer 2019; 19:823. [PMID: 31429730 PMCID: PMC6701111 DOI: 10.1186/s12885-019-6045-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/16/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Natural killer (NK) cell dysfunction following cancer surgery has been shown to promote metastases. Recent studies demonstrate an emerging role for lipids in the modulation of NK cell innate responses. However, the mechanisms involved in lipid modulation of NK cell postoperative anti-tumor function are unknown. This current study will determine whether the lipid accumulation via scavenger receptors on NK cells is responsible for the increase in postoperative metastasis. METHODS Lipid content in mouse and human NK cells was evaluated by flow cytometry. NK cell scavenger receptor (SR) expression was measured by microarray analysis, validated by qRT-PCR and flow cytometry. NK cell ex vivo and in vivo tumor killing was measured by chromium-release and adoptive transfer assays, respectively. The mediating role of surgery-expanded granulocytic myeloid derived suppressor cells (gMDSC) in SR induction on NK cells was evaluated using co-culture assays. RESULTS NK cells in surgery-treated mice demonstrated increased lipid accumulation, which occurred via up-regulation of MSR1, CD36 and CD68. NK cells with high lipid content had diminished ability to lyse tumor targets ex vivo. Adoptive transfer of lipid-laden NK cells into NK cell-deficient mice were unable to protect against a lung tumor challenge. Granulocytic MDSC from surgery-treated mice increased SR expression on NK cells. Colorectal cancer surgical patients showed increased NK cell lipid content, higher CD36 expression, decreased granzyme B and perforin production in addition to reduced cytotoxicity in the postoperative period. CONCLUSIONS Postoperative lipid accumulation promotes the formation of metastases by impairing NK cell function in both preclinical surgical models and human surgical colorectal cancer patient samples. Understanding and targeting the mechanisms underlying lipid accumulation in innate immune NK cells can improve prognosis in cancer surgical patients.
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Affiliation(s)
- Seyedeh Raheleh Niavarani
- Department of Anatomy and Cell Biology, Université de Sherbrooke, Pavillon sur la Recherche Appliqué du Cancer at 3201 rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
| | - Christine Lawson
- Department of Anatomy and Cell Biology, Université de Sherbrooke, Pavillon sur la Recherche Appliqué du Cancer at 3201 rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
| | - Orneala Bakos
- Department of Anatomy and Cell Biology, Université de Sherbrooke, Pavillon sur la Recherche Appliqué du Cancer at 3201 rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
| | - Marie Boudaud
- Department of Pediatrics, Division of Immunology, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Cory Batenchuk
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Samuel Rouleau
- Department of Anatomy and Cell Biology, Université de Sherbrooke, Pavillon sur la Recherche Appliqué du Cancer at 3201 rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
| | - Lee-Hwa Tai
- Department of Anatomy and Cell Biology, Université de Sherbrooke, Pavillon sur la Recherche Appliqué du Cancer at 3201 rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada. .,Centre de Recherche Clinique de Centre Hospitalier de l'Universite de Sherbrooke, Sherbrooke, QC, Canada.
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23
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Cabrera G, Marcipar I. Vaccines and the regulatory arm of the immune system. An overview from the Trypanosoma cruzi infection model. Vaccine 2019; 37:3628-3637. [PMID: 31155420 DOI: 10.1016/j.vaccine.2019.05.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 04/13/2019] [Accepted: 05/03/2019] [Indexed: 01/06/2023]
Abstract
The knowledge that the immune system is composed of a regulatory/suppressor arm added a new point of view to better understand the nature of several pathologies including cancer, transplants, infections and autoimmune diseases. The striking discoveries concerning molecules and cells involved in this kind of regulation were followed by the elucidation of equally notable mechanisms used by several pathogens to manipulate the host immune system. Vaccines against pathogens are an invaluable tool developed to help the immune system cope with a potential infection or prevent disease pathology. Nowadays, there is accumulated evidence indicating that the powerful stimulation capacity of vaccines influences not only the effector arm of the immune system but also cells with regulatory/suppressor capacity, such as myeloid derived suppressor cells (MDSCs) and Foxp3+ regulatory T cells (Tregs). Trypanosoma cruzi (T. cruzi) is a protozoan parasite with a complex life cycle that has evolved several strategies to influence the regulatory immune response. Although diverse vaccine formulations have been able to stimulate the effector response, achieving non-sterilizing protection against T. cruzi, the influence of the vaccine candidates on the regulatory machinery has scarcely been assessed. This fact may not only reveal important information concerning how vaccines may influence cells with regulatory/suppressor capacity but also open the possibility to analyze whether vaccines are able to disrupt the mechanisms used by some pathogens to manipulate the host regulatory circuits. The aim of this review is to summarize and discuss available data related to the role of cellular components, like MDSCs and Foxp3+ Tregs, during T. cruzi infection, and the potential utility of those populations as additional targets for the rational design of vaccines.
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Affiliation(s)
- Gabriel Cabrera
- Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
| | - Iván Marcipar
- Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina
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24
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Gliwiński M, Piotrowska M, Iwaszkiewicz-Grześ D, Urban-Wójciuk Z, Trzonkowski P. Therapy with CD4 +CD25 + T regulatory cells - should we be afraid of cancer? Contemp Oncol (Pozn) 2019; 23:1-6. [PMID: 31061630 PMCID: PMC6500397 DOI: 10.5114/wo.2019.84110] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 03/24/2019] [Indexed: 12/27/2022] Open
Abstract
This review focuses on the role of regulatory T cells (Tregs) in the process of carcinogenesis. The controversy of this issue arose due to the increasing therapeutic use of Tregs in humans (inter alia, in the treatment of autoimmune diseases). It is mainly due to potential dangers related to immunosuppressive activity of these cells, especially regarding cancer. The natural function of regulatory T cells (which is the suppression of excessive activity of the immune system) is purportedly linked to an increased risk of cancer initiation. This work brings together and summarizes the most important reports of researchers dealing with this problem and attempts to explain doubts and fears related to Tregs and their uncertain connection with cancer initiation and progression. It is clearly shown that regulatory T cells are associated with acceleration of existing tumors (they are attracted by microenvironments created by cancer cells) but cannot initiate them on their own.
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Affiliation(s)
- Mateusz Gliwiński
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Zuzanna Urban-Wójciuk
- International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
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25
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The level of myeloid-derived suppressor cells positively correlates with regulatory T cells in the blood of children with transient hypogammaglobulinaemia of infancy. Cent Eur J Immunol 2019; 43:413-420. [PMID: 30799989 PMCID: PMC6384417 DOI: 10.5114/ceji.2018.81359] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 12/04/2018] [Indexed: 12/21/2022] Open
Abstract
Introduction Transient hypogammaglobulinaemia of infancy (THI) is a primary immunodeficiency characterised by low levels of immunoglobulin G (often with concomitant decrease of IgA and sometimes also of IgM) with still unknown exact reason. A delayed normalisation of the immunoglobulin level in THI may be associated with a transiently elevated number of regulatory T cells (Treg). Although in cancer and chronic inflammation it was shown that the level of Treg cells can be increased by myeloid-derived suppressor cells (MDSCs), until now no studies have been performed in the context of the role of MDSCs in THI and their correlation with Treg cells. Consequently, we aimed to determine the occurrence of MDSCs in the peripheral blood of children with THI and correlate their level with the level of Treg cells. Material and methods Flow cytometry analyses of Mo-MDSCs and Gr-MDSCs, characterised as HLA-DR–CD11b+CD15–CD14+ and HLA-DR–CD11b+CD15+CD14–, respectively, and Treg (CD4+CD25+Foxp3+) cells were performed. Results The proportion of Mo-MDSCs and Gr-MDSCs was significantly higher in the group of THI patients with elevated level of Treg cells (from the 95% confidence interval level of healthy controls). The cells with Mo-MDSC and Gr-MDSC characteristics positively correlated with the level of Treg cells. Moreover, children with a higher proportion of circulating Treg cells, and thereby higher level of MDSCs, showed delayed normalisation of IgG level and recovery. Conclusions These findings show for the first time that MDSCs may be involved in the pathomechanism of THI, probably acting through the induction of Treg cells.
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26
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The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction. Cancers (Basel) 2018; 11:cancers11010002. [PMID: 30577463 PMCID: PMC6356325 DOI: 10.3390/cancers11010002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 12/10/2018] [Accepted: 12/17/2018] [Indexed: 12/22/2022] Open
Abstract
Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis.
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27
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Su X, Fan Y, Yang L, Huang J, Qiao F, Fang Y, Wang J. Dexmedetomidine expands monocytic myeloid-derived suppressor cells and promotes tumour metastasis after lung cancer surgery. J Transl Med 2018; 16:347. [PMID: 30537999 PMCID: PMC6288950 DOI: 10.1186/s12967-018-1727-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 12/05/2018] [Indexed: 12/22/2022] Open
Abstract
Background Dexmedetomidine (DEX) has been reported to promote tumour metastases. However the underlying mechanisms remain unclear. The purpose of this study was to investigate whether DEX promotes tumour metastasis by inducing myeloid-derived suppressor cells (MDSC) in the context of surgery. Methods DEX was given to lung cancer patients and its effects on expansion of monocytic MDSC (M-MDSC) were studied in the context of surgery. Spontaneous tumour metastasis was induced in C57BL/6 mice and the effects of DEX on M-MDSC expansion and metastasis formation were assessed. Results DEX increased CD11b+CD33+HLA-DR–CD14+ M-MDSC in lung cancer patients after thoractomy. DEX-induced M-MDSC, in addition to have immunosuppressive activity, were more efficient in producing VEGF. Expansion of M-MDSC by DEX involved α2-adrenergic receptor. Using an experimental tumour metastasis mouse model, we demonstrated that the numbers of metastases on lung surface and CD11b+Ly6ChighLy6G− M-MDSC during postoperative period were enhanced in DEX-treated mice. Promotion of tumour metastasis by DEX-induced M-MDSC involved VEGF, a key factor for tumour angiogenesis. Conclusions DEX induces the proliferation of M-MDSC during postoperative period in lung cancer patients and this cell population is qualified with potent proangiogenic ability. Treatment of mice with DEX expands M-MDSC and promotes tumour metastasis through the increasing production of VEGF. Electronic supplementary material The online version of this article (10.1186/s12967-018-1727-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaosan Su
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, 650011, Yunnan, People's Republic of China
| | - Yaodong Fan
- Department of Neurosurgery, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), 519 Kun Zhou Road, Kunming, 650118, Yunnan, People's Republic of China
| | - Liu Yang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, 650011, Yunnan, People's Republic of China
| | - Jie Huang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Fei Qiao
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Yu Fang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Jun Wang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, 650032, Yunnan, People's Republic of China.
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28
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Burkert SC, Shurin GV, White DL, He X, Kapralov AA, Kagan VE, Shurin MR, Star A. Targeting myeloid regulators by paclitaxel-loaded enzymatically degradable nanocups. NANOSCALE 2018; 10:17990-18000. [PMID: 30226240 PMCID: PMC6563927 DOI: 10.1039/c8nr04437f] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Tumor microenvironment is characterized by immunosuppressive mechanisms associated with the accumulation of immune regulatory cells - myeloid-derived suppressor cells (MDSC). Therapeutic depletion of MDSC has been associated with inhibition of tumor growth and therefore represents an attractive approach to cancer immunotherapy. MDSC in cancer are characterized by enhanced enzymatic capacity to generate reactive oxygen and nitrogen species (RONS) which have been shown to effectively degrade carbonaceous materials. We prepared enzymatically openable nitrogen-doped carbon nanotube cups (NCNC) corked with gold nanoparticles and loaded with paclitaxel as a therapeutic cargo. Loading and release of paclitaxel was confirmed through electron microscopy, Raman spectroscopy and LC-MS analysis. Under the assumption that RONS generated by MDSCs can be utilized as a dual targeting and oxidative degradation mechanism for NCNC, here we report that systemic administration of paclitaxel loaded NCNC delivers paclitaxel to circulating and lymphoid tissue MDSC resulting in the inhibition of growth of tumors (B16 melanoma cells inoculated into C57BL/6 mice) in vivo. Tumor growth inhibition was associated with decreased MDSC accumulation quantified by flow cytometry that correlated with bio-distribution of gold-corked NCNC resolved by ICP-MS detection of residual gold in mouse tissue. Thus, we developed a novel immunotherapeutic approach based on unique nanodelivery vehicles, which can be loaded with therapeutic agents that are released specifically in MDSC via NCNC selective enzymatic "opening" affecting change in the tumor microenvironment.
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Affiliation(s)
- Seth C Burkert
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
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29
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Angka L, Martel AB, Kilgour M, Jeong A, Sadiq M, de Souza CT, Baker L, Kennedy MA, Kekre N, Auer RC. Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery. Ann Surg Oncol 2018; 25:3747-3754. [DOI: 10.1245/s10434-018-6691-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Indexed: 01/27/2023]
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30
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Yoshida M, Taguchi A, Kawana K, Ogishima J, Adachi K, Kawata A, Nakamura H, Sato M, Fujimoto A, Inoue T, Tomio K, Mori M, Nagamatsu T, Arimoto T, Koga K, Hiraike OW, Oda K, Kiyono T, Osuga Y, Fujii T. Intraperitoneal neutrophils activated by KRAS-induced ovarian cancer exert antitumor effects by modulating adaptive immunity. Int J Oncol 2018; 53:1580-1590. [PMID: 30066851 PMCID: PMC6086631 DOI: 10.3892/ijo.2018.4504] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/04/2018] [Indexed: 12/15/2022] Open
Abstract
Increased neutrophil counts are a hallmark of a poor prognosis for cancer. We previously reported that KRAS promoted tumorigenesis and increased neutrophil counts in a mouse peritoneal cancer model. In the current study, we evaluated the role of increased neutrophils in cancer progression, as well as their influence on the intraperitoneal microenvironment. A mouse peritoneal cancer model was established using the KRAS-transduced mouse ovarian cancer cell line, ID8-KRAS. Neutrophil function was assessed by neutrophil depletion in ID8-KRAS mice. Neutrophil depletion markedly accelerated tumor formation; this was accompanied by an increase in interleukin-6 concentrations in ascites. Neutrophil depletion significantly decreased the amount of local and systemic CD8+ T cells, while increasing the amount of local CD4+ T cells, accompanied by an increased amount of monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) (P<0.05). The roles of peritoneal neutrophils (PENs) in CD8+ T cell activation were assessed in vitro. PENs of ID8-KRAS mice had a strong potential to enhance T cell proliferation with a higher expression of the T cell costimulatory molecules OX40 ligand (OX40L) and 4-1BB ligand (4-1BBL), as compared with peripheral blood neutrophils (PBNs). These findings suggest that neutrophils recruited into the KRAS-induced tumor microenvironment (TME) have antitumor properties with the potential to modulate the numbers of M-MDSCs and Tregs and activate CD8+ T cells through T cell costimulatory molecules.
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Affiliation(s)
- Mitsuyo Yoshida
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Juri Ogishima
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Katsuyuki Adachi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Akira Kawata
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Hiroe Nakamura
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Masakazu Sato
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Asaha Fujimoto
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tomoko Inoue
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kensuke Tomio
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Mayuyo Mori
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Takeshi Nagamatsu
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Takahide Arimoto
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kaori Koga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Osamu Wada Hiraike
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Katsutoshi Oda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tohru Kiyono
- Division of Virology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
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Tai LH, Alkayyal AA, Leslie AL, Sahi S, Bennett S, Tanese de Souza C, Baxter K, Angka L, Xu R, Kennedy MA, Auer RC. Phosphodiesterase-5 inhibition reduces postoperative metastatic disease by targeting surgery-induced myeloid derived suppressor cell-dependent inhibition of Natural Killer cell cytotoxicity. Oncoimmunology 2018; 7:e1431082. [PMID: 29872554 DOI: 10.1080/2162402x.2018.1431082] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 01/13/2018] [Accepted: 01/18/2018] [Indexed: 12/27/2022] Open
Abstract
Cancer surgery while necessary for primary tumor removal, has been shown to induce immune suppression and promote metastases in preclinical models and human cancer surgery patients. Activating the immune system and reversing immunosuppression have emerged as promising ways to treat cancer and they can be safely employed in the perioperative period. In this study, we evaluated the immunotherapeutic potential of phosphodiesterase-5 (PDE-5) inhibitors to target surgery-induced myeloid-derived suppressor cells (MDSC) and restore natural killer (NK) cell function in the clinically relevant perioperative period. Immunocompetent murine tumor models of major surgery were used to characterize the functional suppression of surgery-induced MDSC and to assess the in vivo efficacy of perioperative PDE5 inhibition. In cancer surgery patients with abdominal malignancies, we assessed postoperative NK cell function following co-culture with MDSC and PDE5 inhibition. Perioperative PDE5 inhibition reverses surgery-induced immunosuppression. In particular, sildenafil reduces surgery-derived granulocytic-MDSC (gMDSC) function through downregulation of arginase 1 (ARG1), IL4Ra and reactive oxygen species (ROS) expression, enabling NK cell antitumor cytotoxicity and reducing postoperative disease recurrence. By removing surgery-derived immunosuppressive mechanisms of MDSCs, sildenafil can be combined with the administration of perioperative influenza vaccination which targets NK cells to reduce postoperative metastasis. Importantly, sildenafil reverses MDSC suppression in cancer surgery patients. These findings demonstrate that PDE5 inhibitors reduce postoperative metastasis by their ability to inhibit surgery-induced MDSC. Further clinical studies are warranted to investigate the immunotherapeutic role of PDE5 inhibitors in combination with cancer surgery.
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Affiliation(s)
- Lee-Hwa Tai
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Almohanad A Alkayyal
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.,Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Tabuk, Saudi Arabia
| | - Amanda L Leslie
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Shalini Sahi
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Sean Bennett
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Surgery, University of Ottawa, Ottawa, ON, Canada
| | | | - Katherine Baxter
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Leonard Angka
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Rebecca Xu
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Michael A Kennedy
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Rebecca C Auer
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.,Department of Surgery, University of Ottawa, Ottawa, ON, Canada
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32
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Martinenaite E, Mortensen REJ, Hansen M, Orebo Holmström M, Munir Ahmad S, Grønne Dahlager Jørgensen N, Met Ö, Donia M, Svane IM, Andersen MH. Frequent adaptive immune responses against arginase-1. Oncoimmunology 2017; 7:e1404215. [PMID: 29399404 DOI: 10.1080/2162402x.2017.1404215] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/25/2017] [Accepted: 11/07/2017] [Indexed: 01/09/2023] Open
Abstract
The enzyme arginase-1 reduces the availability of arginine to tumor-infiltrating immune cells, thus reducing T-cell functionality in the tumor milieu. Arginase-1 is expressed by some cancer cells and by immune inhibitory cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and its expression is associated with poor prognosis. In the present study, we divided the arginase-1 protein sequence into overlapping 20-amino-acid-long peptides, generating a library of 31 peptides covering the whole arginase-1 sequence. Reactivity towards this peptide library was examined in PBMCs from cancer patients and healthy individuals. IFNγ ELISPOT revealed frequent immune responses against multiple arginase-1-derived peptides. We further identified a hot-spot region within the arginase-1 protein sequence containing multiple epitopes recognized by T cells. Next, we examined in vitro-expanded tumor-infiltrating lymphocytes (TILs) isolated from melanoma patients, and detected arginase-1-specific T cells that reacted against epitopes from the hot-spot region. Arginase-1-specific CD4+T cells could be isolated and expanded from peripheral T cell pool of a patient with melanoma, and further demonstrated the specificity and reactivity of these T cells. Overall, we showed that arginase-1-specific T cells were capable of recognizing arginase-1-expressing cells. The activation of arginase-1-specific T cells by vaccination is an attractive approach to target arginase-1-expressing malignant cells and inhibitory immune cells. In the clinical setting, the induction of arginase-1-specific immune responses could induce or increase Th1 inflammation at the sites of tumors that are otherwise excluded due to infiltration with MDSCs and TAMs.
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Affiliation(s)
- Evelina Martinenaite
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | | | - Morten Hansen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Morten Orebo Holmström
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Shamaila Munir Ahmad
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | | | - Özcan Met
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark.,Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Marco Donia
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Mads Hald Andersen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Hematology, Zealand University Hospital, Roskilde, Denmark
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33
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Angka L, Khan ST, Kilgour MK, Xu R, Kennedy MA, Auer RC. Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery. Int J Mol Sci 2017; 18:ijms18081787. [PMID: 28817109 PMCID: PMC5578175 DOI: 10.3390/ijms18081787] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/13/2017] [Accepted: 08/14/2017] [Indexed: 02/06/2023] Open
Abstract
The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery.
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Affiliation(s)
- Leonard Angka
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
| | - Sarwat T Khan
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
| | - Marisa K Kilgour
- Deeley Research Centre, BC Cancer Agency, Victoria, BC V8R 6V5, Canada.
| | - Rebecca Xu
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
| | - Michael A Kennedy
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
| | - Rebecca C Auer
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
- Department of Surgery, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
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