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Tumor-Infiltrating Neutrophils and Non-Classical Monocytes May Be Potential Therapeutic Targets for HER2 negative Gastric Cancer

박지현|정기훈|이혁준|김덕기|공성호|양한광|박도중|정주희
대한면역학회 (The Korean Association of Immunologists)|2021.08|Immune Network|제21권 제4호|pp. 1-16|DOI 10.4110/in.2021.21.e31

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Gastric cancerImmunotherapyNeutrophilsTumor microenvironmentNon-classical monocytes

초록

Gastric cancer (GC) is the fourth most common cause of cancer-related death globally. The classification of advanced GC (AGC) according to molecular features has recently led to effective personalized cancer therapy for some patients. Specifically, AGC patients whose tumor cells express high levels of human epidermal growth factor receptor 2 (HER2) can now benefit from trastuzumab, a humanized monoclonal Ab that targets HER2. However, patients with HER2negative AGC receive limited clinical benefit from this treatment. To identify potential immune therapeutic targets in HER2negative AGC, we obtained 40 fresh AGC specimens immediately after surgical resections and subjected the CD45+ immune cells in the tumor microenvironment to multi-channel/multi-panel flow cytometry analysis. Here, we report that HER2 negativity associated with reduced overall survival (OS) and greater tumor infiltration with neutrophils and non-classical monocytes. The potential pro-tumoral activities of these cell types were confirmed by the fact that high expression of neutrophil or non-classical monocyte signature genes in the gastrointestinal tumors in The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases associated with worse OS on Kaplan-Meir plots relative to tumors with low expression of these signature genes. Moreover, advanced stage disease in the AGCs of our patients associated with greater tumor frequencies of neutrophils and non-classical monocytes than early stage disease. Thus, our study suggests that these 2 myeloid populations may serve as novel therapeutic targets for HER2negative AGC.

Abstract

Gastric cancer (GC) is the fourth most common cause of cancer-related death globally. The classification of advanced GC (AGC) according to molecular features has recently led to effective personalized cancer therapy for some patients. Specifically, AGC patients whose tumor cells express high levels of human epidermal growth factor receptor 2 (HER2) can now benefit from trastuzumab, a humanized monoclonal Ab that targets HER2. However, patients with HER2negative AGC receive limited clinical benefit from this treatment. To identify potential immune therapeutic targets in HER2negative AGC, we obtained 40 fresh AGC specimens immediately after surgical resections and subjected the CD45+ immune cells in the tumor microenvironment to multi-channel/multi-panel flow cytometry analysis. Here, we report that HER2 negativity associated with reduced overall survival (OS) and greater tumor infiltration with neutrophils and non-classical monocytes. The potential pro-tumoral activities of these cell types were confirmed by the fact that high expression of neutrophil or non-classical monocyte signature genes in the gastrointestinal tumors in The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases associated with worse OS on Kaplan-Meir plots relative to tumors with low expression of these signature genes. Moreover, advanced stage disease in the AGCs of our patients associated with greater tumor frequencies of neutrophils and non-classical monocytes than early stage disease. Thus, our study suggests that these 2 myeloid populations may serve as novel therapeutic targets for HER2negative AGC.

참고문헌 (55)

  1. Etemadi A, "The global, regional, and national burden of stomach cancer in 195 countries, 1990–2017 : a systematic analysis for the Global Burden of Disease study 2017", Lancet Gastroenterol Hepatol, 5, pp.42~54 (2020)
  2. Sung H, "Global cancer statistics 2020 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries", CA Cancer J Clin, 71, pp.209~249 (2021)
  3. Kono K, "Current status of immune checkpoint inhibitors for gastric cancer", Gastric Cancer, 23, pp.565~578 (2020)
  4. Shi WJ, "Molecular mechanisms of chemoresistance in gastric cancer", World J Gastrointest Oncol, 8, pp.673~681 (2016)
  5. Masuishi T, "FOLFOX as first-line therapy for gastric cancer with severe peritoneal metastasis", Anticancer Res, 37, pp.7037~7042 (2017)
  6. Madden EC, "Tumour cell secretome in chemoresistance and tumour recurrence", Trends Cancer, 6, pp.489~505 (2020)
  7. Joshi SS, "Current treatment and recent progress in gastric cancer", CA Cancer J Clin, 71, pp.264~279 (2021)
  8. Tsapralis D, "Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology", World J Gastroenterol, 18, pp.150~155 (2012)
  9. Shitara K, "Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer", N Engl J Med, 382, pp.2419~2430 (2020)
  10. Yang YM, "Advances in targeted therapy for esophageal cancer", Signal Transduct Target Ther, 5, pp.229~ (2020)
  11. Vu T, "Trastuzumab : updated mechanisms of action and resistance in breast cancer", Front Oncol, 2, pp.62~ (2012)
  12. Yao Y, "Maintenance treatment in advanced HER2-negative gastric cancer", Clin Transl Oncol, 22, pp.2206~2212 (2020)
  13. Jeong J, "Context drives diversification of monocytes and neutrophils in orchestrating the tumor microenvironment", Front Immunol, 10, pp.1817~ (2019)
  14. Barnes TA, "HYPE or HOPE : the prognostic value of infiltrating immune cells in cancer", Br J Cancer, 117, pp.451~460 (2017)
  15. Waldman AD, "A guide to cancer immunotherapy : from T cell basic science to clinical practice", Nat Rev Immunol, 20, pp.651~668 (2020)
  16. Seongju Jeong, "Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy", Immune Network, 20(1), pp.1~20 (2020), 대한면역학회[DOI]
  17. 권민석, "Two-Round Mixed Lymphocyte Reaction for Evaluation of the Functional Activities of Anti-PD-1 and Immunomodulators", Immune Network, 18(6), pp.1~11 (2018), 대한면역학회[DOI]
  18. 권다솔, "IL-17-Producing Cells in Tumor Immunity: Friends or Foes?", Immune Network, 20(1), pp.1~20 (2020), 대한면역학회[DOI]
  19. Bonaventura P, "Cold tumors : a therapeutic challenge for immunotherapy", Front Immunol, 10, pp.168~ (2019)
  20. Restifo NP, "Acquired resistance to immunotherapy and future challenges", Nat Rev Cancer, 16, pp.121~126 (2016)
  21. Sejin Oh, "Far Beyond Cancer Immunotherapy: Reversion of Multi-Malignant Phenotypes of Immunotherapeutic-Resistant Cancer by Targeting the NANOG Signaling Axis", Immune Network, 20(1), pp.1~11 (2020), 대한면역학회[DOI]
  22. Sharma P, "Primary, adaptive, and acquired resistance to cancer immunotherapy", Cell, 168, pp.707~723 (2017)
  23. Jung K, "Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer", Proc Natl Acad Sci U S A, 114, pp.10455~10460 (2017)
  24. Jung K, "Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy", J Clin Invest, 127, pp.3039~3051 (2017)
  25. Tang Z, "GEPIA2 : an enhanced web server for large-scale expression profiling and interactive analysis", Nucleic Acids Res, 47, pp.W556~W560 (2019)
  26. Szász AM, "Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1, 065patients", Oncotarget, 7, pp.49322~49333 (2016)
  27. Nagy Á, "Pancancer survival analysis of cancer hallmark genes", Sci Rep, 11, pp.6047~ (2021)
  28. Bertani FR, "Classification of M1", M2-polarized human macrophages by label-free hyperspectral reflectance confocal microscopy and multivariate analysis, 2017, pp.7, 8965~
  29. Azizi E, "Single-cell map of diverse immune phenotypes in the breast tumor microenvironment", Cell, 174, pp.1293.e36~1308.e36 (2018)
  30. Zhang L, "Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer", Cell, 181, pp.442.e29~459.e29 (2020)
  31. Shibutani M, "A high preoperative neutrophil-to-lymphocyte ratio is associated with poor survival in patients with colorectal cancer", Anticancer Res, 33, pp.3291~3294 (2013)
  32. Howard R, "Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer", Sci Rep, 9, pp.19673~ (2019)
  33. Zhao JJ, "The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection", PLoS One, 7, pp.e33655~ (2012)
  34. Plebanek MP, "Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche", Nat Commun, 8, pp.1319~ (2017)
  35. Lavin Y, "Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses", Cell, 169, pp.750~765.e17 (2017)
  36. Kubo H, "Primary tumors limit metastasis formation through induction of IL15-mediated cross-talk between patrolling monocytes and NK cells", Cancer Immunol Res, 5, pp.812~820 (2017)
  37. Romano E, "Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients", Proc Natl Acad Sci U S A, 112, pp.6140~6145 (2015)
  38. Hanna RN, "Patrolling monocytes control tumor metastasis to the lung", Science, 350, pp.985~990 (2015)
  39. Sidibe A, "Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours", Nat Commun, 9, pp.355~ (2018)
  40. Coffelt SB, "Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions", Cancer Res, 70, pp.5270~5280 (2010)
  41. De Palma M, "Tie2-expressing monocytes : regulation of tumor angiogenesis and therapeutic implications", Trends Immunol, 28, pp.519~524 (2007)
  42. De Palma M, "Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells", Nat Med, 9, pp.789~795 (2003)
  43. Murdoch C, "Expression of Tie-2 by human monocytes and their responses to angiopoietin-2", J Immunol, 178, pp.7405~7411 (2007)
  44. Decatris MP, "Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer", Future Oncol, 12, pp.1805~1822 (2016)
  45. Bai R, "Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors", Biomark Res, 8, pp.34~ (2020)
  46. Murciano-Goroff YR, "The future of cancer immunotherapy : microenvironmenttargeting combinations", Cell Res, 30, pp.507~519 (2020)
  47. Venteicher AS, "Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by singlecell RNA-seq", Science, 355, pp.eaai8478~ (2017)
  48. Chevrier S, "An immune atlas of clear cell renal cell carcinoma", Cell, 169, pp.736~749.e18 (2017)
  49. Gubin MM, "High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy", Cell, 175, pp.1014~1030 (2018)
  50. Zhang Q, "Landscape and dynamics of single immune cells in hepatocellular carcinoma", Cell, 179, pp.829~845.e20 (2019)
  51. Binnewies M, "Unleashing type-2 dendritic cells to drive protective antitumor CD4+T cell immunity", Cell, 177, pp.556~571.e16 (2019)
  52. Zilionis R, "Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species", Immunity, 50, pp.1317~1334.e10 (2019)
  53. Sathe A, "Single-cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment", Clin Cancer Res, 26, pp.2640~2653 (2020)
  54. Kim N, "Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma", Nat Commun, 11, pp.2285~ (2020)
  55. Alshetaiwi H, "Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics", Sci Immunol, 5, pp.eaay6017~ (2020)

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