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Tumor-Infiltrating Neutrophils and Non-Classical Monocytes May Be Potential Therapeutic Targets for HER2negative Gastric Cancer

  • Juhee Jeong (Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Duk Ki Kim (Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Ji-Hyeon Park (Department of Surgery, Seoul National University Hospital) ;
  • Do Joong Park (Department of Surgery, Seoul National University Hospital) ;
  • Hyuk-Joon Lee (Department of Surgery, Seoul National University Hospital) ;
  • Han-Kwang Yang (Department of Surgery, Seoul National University Hospital) ;
  • Seong-Ho Kong (Department of Surgery, Seoul National University Hospital) ;
  • Keehoon Jung (Department of Anatomy and Cell Biology, Seoul National University College of Medicine)
  • Received : 2021.07.07
  • Accepted : 2021.08.10
  • Published : 2021.08.31
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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.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1C1C1015062) (K.J.), by the cooperative Research Program of Basic Medical Science and Clinical Science from the Seoul National University College of Medicine (No. 800-20190261) (K.J.)/(No. 800-20190262) (H.K.Y.), by the SNUH Research Fund 03-2018-0290 (K.J.), by the Creative-Pioneering Researchers Program through Seoul National University (SNU) (K.J.), and by the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the MSIT (NRF-2020R1A4A1017515) (K.J.).

References

  1. Etemadi A, Safiri S, Sepanlou SG, Ikuta K, Bisignano C, Shakeri R, Amani M, Fitzmaurice C, Nixon M, Abbasi N, et al. 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 2020;5:42-54. https://doi.org/10.1016/S2468-1253(19)30328-0
  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249. https://doi.org/10.3322/caac.21660
  3. Kono K, Nakajima S, Mimura K. Current status of immune checkpoint inhibitors for gastric cancer. Gastric Cancer 2020;23:565-578. https://doi.org/10.1007/s10120-020-01090-4
  4. Shi WJ, Gao JB. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016;8:673-681. https://doi.org/10.4251/wjgo.v8.i9.673
  5. Masuishi T, Kadowaki S, Kondo M, Komori A, Sugiyama K, Mitani S, Honda K, Narita Y, Taniguchi H, Ura T, et al. FOLFOX as first-line therapy for gastric cancer with severe peritoneal metastasis. Anticancer Res 2017;37:7037-7042. https://doi.org/10.21873/anticanres.12174
  6. Madden EC, Gorman AM, Logue SE, Samali A. Tumour cell secretome in chemoresistance and tumour recurrence. Trends Cancer 2020;6:489-505. https://doi.org/10.1016/j.trecan.2020.02.020
  7. Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin 2021;71:264-279. https://doi.org/10.3322/caac.21657
  8. Tsapralis D, Panayiotides I, Peros G, Liakakos T, Karamitopoulou E. Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology. World J Gastroenterol 2012;18:150-155. https://doi.org/10.3748/wjg.v18.i2.150
  9. Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 2020;382:2419-2430. https://doi.org/10.1056/NEJMoa2004413
  10. Yang YM, Hong P, Xu WW, He QY, Li B. Advances in targeted therapy for esophageal cancer. Signal Transduct Target Ther 2020;5:229.
  11. Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 2012;2:62.
  12. Yao Y, Deng R, Liao D, Xie H, Zuo J, Jia Y, Kong F. Maintenance treatment in advanced HER2-negative gastric cancer. Clin Transl Oncol 2020;22:2206-2212. https://doi.org/10.1007/s12094-020-02379-7
  13. Jeong J, Suh Y, Jung K. Context drives diversification of monocytes and neutrophils in orchestrating the tumor microenvironment. Front Immunol 2019;10:1817.
  14. Barnes TA, Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer 2017;117:451-460. https://doi.org/10.1038/bjc.2017.220
  15. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20:651-668. https://doi.org/10.1038/s41577-020-0306-5
  16. Jeong S, Park SH. Co-stimulatory receptors in cancers and their implications for cancer immunotherapy. Immune Netw 2020;20:e3.
  17. Kwon M, Choi YJ, Sa M, Park SH, Shin EC. Two-round mixed lymphocyte reaction for evaluation of the functional activities of anti-PD-1 and immunomodulators. Immune Netw 2018;18:e45.
  18. Kuen DS, Kim BS, Chung Y. IL-17-producing cells in tumor immunity: friends or foes? Immune Netw 2020;20:e6.
  19. Bonaventura P, Shekarian T, Alcazer V, Valladeau-Guilemond J, Valsesia-Wittmann S, Amigorena S, Caux C, Depil S. Cold tumors: a therapeutic challenge for immunotherapy. Front Immunol 2019;10:168.
  20. Restifo NP, Smyth MJ, Snyder A. Acquired resistance to immunotherapy and future challenges. Nat Rev Cancer 2016;16:121-126. https://doi.org/10.1038/nrc.2016.2
  21. Oh SJ, Lee J, Kim Y, Song KH, Cho E, Kim M, Jung H, Kim TW. Far beyond cancer immunotherapy: reversion of multi-malignant phenotypes of immunotherapeutic-resistant cancer by targeting the NANOG signaling axis. Immune Netw 2020;20:e7.
  22. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017;168:707-723. https://doi.org/10.1016/j.cell.2017.01.017
  23. Jung K, Heishi T, Incio J, Huang Y, Beech EY, Pinter M, Ho WW, Kawaguchi K, Rahbari NN, Chung E, et al. Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. Proc Natl Acad Sci U S A 2017;114:10455-10460. https://doi.org/10.1073/pnas.1710754114
  24. Jung K, Heishi T, Khan OF, Kowalski PS, Incio J, Rahbari NN, Chung E, Clark JW, Willett CG, Luster AD, et al. Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest 2017;127:3039-3051. https://doi.org/10.1172/JCI93182
  25. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res 2019;47:W556-W560. https://doi.org/10.1093/nar/gkz430
  26. Szasz AM, Lanczky A, Nagy A, Forster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabo A, Gyorffy B. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget 2016;7:49322-49333. https://doi.org/10.18632/oncotarget.10337
  27. Nagy A, Munkacsy G, Gyorffy B. Pancancer survival analysis of cancer hallmark genes. Sci Rep 2021;11:6047.
  28. Bertani FR, Mozetic P, Fioramonti M, Iuliani M, Ribelli G, Pantano F, Santini D, Tonini G, Trombetta M, Businaro L, et al. Classification of M1/M2-polarized human macrophages by label-free hyperspectral reflectance confocal microscopy and multivariate analysis. Sci Rep 2017;7:8965.
  29. Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, Nainys J, Wu K, Kiseliovas V, Setty M, et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 2018;174:1293-1308.e36. https://doi.org/10.1016/j.cell.2018.05.060
  30. Zhang L, Li Z, Skrzypczynska KM, Fang Q, Zhang W, O'Brien SA, He Y, Wang L, Zhang Q, Kim A, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 2020;181:442-459.e29. https://doi.org/10.1016/j.cell.2020.03.048
  31. Shibutani M, Maeda K, Nagahara H, Noda E, Ohtani H, Nishiguchi Y, Hirakawa K. A high preoperative neutrophil-to-lymphocyte ratio is associated with poor survival in patients with colorectal cancer. Anticancer Res 2013;33:3291-3294.
  32. Howard R, Kanetsky PA, Egan KM. Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer. Sci Rep 2019;9:19673.
  33. Zhao JJ, Pan K, Wang W, Chen JG, Wu YH, Lv L, Li JJ, Chen YB, Wang DD, Pan QZ, et al. The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS One 2012;7:e33655.
  34. Plebanek MP, Angeloni NL, Vinokour E, Li J, Henkin A, Martinez-Marin D, Filleur S, Bhowmick R, Henkin J, Miller SD, et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat Commun 2017;8:1319.
  35. Lavin Y, Kobayashi S, Leader A, Amir ED, Elefant N, Bigenwald C, Remark R, Sweeney R, Becker CD, Levine JH, et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 2017;169:750-765.e17. https://doi.org/10.1016/j.cell.2017.04.014
  36. Kubo H, Mensurado S, Goncalves-Sousa N, Serre K, Silva-Santos B. Primary tumors limit metastasis formation through induction of IL15-mediated cross-talk between patrolling monocytes and NK cells. Cancer Immunol Res 2017;5:812-820. https://doi.org/10.1158/2326-6066.CIR-17-0082
  37. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P, Speiser DE. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A 2015;112:6140-6145. https://doi.org/10.1073/pnas.1417320112
  38. Hanna RN, Cekic C, Sag D, Tacke R, Thomas GD, Nowyhed H, Herrley E, Rasquinha N, McArdle S, Wu R, et al. Patrolling monocytes control tumor metastasis to the lung. Science 2015;350:985-990. https://doi.org/10.1126/science.aac9407
  39. Sidibe A, Ropraz P, Jemelin S, Emre Y, Poittevin M, Pocard M, Bradfield PF, Imhof BA. Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours. Nat Commun 2018;9:355.
  40. Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y, et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 2010;70:5270-5280. https://doi.org/10.1158/0008-5472.CAN-10-0012
  41. De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 2007;28:519-524. https://doi.org/10.1016/j.it.2007.09.004
  42. De Palma M, Venneri MA, Roca C, Naldini L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 2003;9:789-795. https://doi.org/10.1038/nm871
  43. Murdoch C, Tazzyman S, Webster S, Lewis CE. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol 2007;178:7405-7411. https://doi.org/10.4049/jimmunol.178.11.7405
  44. Decatris MP, O'Byrne KJ. Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer. Future Oncol 2016;12:1805-1822. https://doi.org/10.2217/fon-2016-0086
  45. Bai R, Lv Z, Xu D, Cui J. Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark Res 2020;8:34.
  46. Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res 2020;30:507-519. https://doi.org/10.1038/s41422-020-0337-2
  47. Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, Hovestadt V, Escalante LE, Shaw ML, Rodman C, et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 2017;355:eaai8478.
  48. Chevrier S, Levine JH, Zanotelli VRT, Silina K, Schulz D, Bacac M, Ries CH, Ailles L, Jewett MAS, Moch H, et al. An immune atlas of clear cell renal cell carcinoma. Cell 2017;169:736-749.e18. https://doi.org/10.1016/j.cell.2017.04.016
  49. Gubin MM, Esaulova E, Ward JP, Malkova ON, Runci D, Wong P, Noguchi T, Arthur CD, Meng W, Alspach E, et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 2018;175:1014-1030.e19. https://doi.org/10.1016/j.cell.2018.09.030
  50. Zhang Q, He Y, Luo N, Patel SJ, Han Y, Gao R, Modak M, Carotta S, Haslinger C, Kind D, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 2019;179:829-845.e20. https://doi.org/10.1016/j.cell.2019.10.003
  51. Binnewies M, Mujal AM, Pollack JL, Combes AJ, Hardison EA, Barry KC, Tsui J, Ruhland MK, Kersten K, Abushawish MA, et al. Unleashing type-2 dendritic cells to drive protective antitumor CD4+  T cell immunity. Cell 2019;177:556-571.e16. https://doi.org/10.1016/j.cell.2019.02.005
  52. Zilionis R, Engblom C, Pfirschke C, Savova V, Zemmour D, Saatcioglu HD, Krishnan I, Maroni G, Meyerovitz CV, Kerwin CM, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 2019;50:1317-1334.e10. https://doi.org/10.1016/j.immuni.2019.03.009
  53. Sathe A, Grimes SM, Lau BT, Chen J, Suarez C, Huang RJ, Poultsides G, Ji HP. Single-cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment. Clin Cancer Res 2020;26:2640-2653. https://doi.org/10.1158/1078-0432.CCR-19-3231
  54. Kim N, Kim HK, Lee K, Hong Y, Cho JH, Choi JW, Lee JI, Suh YL, Ku BM, Eum HH, et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat Commun 2020;11:2285.
  55. Alshetaiwi H, Pervolarakis N, McIntyre LL, Ma D, Nguyen Q, Rath JA, Nee K, Hernandez G, Evans K, Torosian L, et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci Immunol 2020;5:eaay6017.