Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Immune Regulatory Function of Cancer-Associated Fibroblasts in Non-small Cell Lung Cancer

  • Hyewon Lee (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University) ;
  • Mina Hwang (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Seonae Jang (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Sang-Won Um (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University)
  • Received : 2022.09.17
  • Accepted : 2023.06.18
  • Published : 2023.10.31
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Abstract

Background: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and significantly contribute to immune evasion. We investigated the effects of CAFs on the immune function of CD4+ and CD8+ T cells in non-small cell lung cancer (NSCLC). Methods: We isolated CAFs and normal fibroblasts (NFs) from tumors and normal lung tissues of NSCLC patients, respectively. CAFs were co-cultured with activated T cells to evaluate their immune regulatory function. We investigated the effect of CAF conditioned medium (CAF-CM) on the cytotoxicity of T cells. CAFs were also co-cultured with activated peripheral blood mononuclear cells and further incubated with cyclooxygenase-2 (COX2) inhibitors to investigate the potential role of COX2 in immune evasion. Results: CAFs and NFs were isolated from the lung tissues (n=8) and lymph nodes (n=3) of NSCLC patients. Immune suppressive markers, such as COX2 and programmed death-ligand 1 (PD-L1), were increased in CAFs after co-culture with activated T cells. Interestingly, CAFs promoted the expression of programmed death-1 in CD4+ and CD8+ T cells, and strongly inhibited T cell proliferation in allogenic and autologous pairs of CAFs and T cells. CAF-CM decreased the cytotoxicity of T cells. COX2 inhibitors partially restored the proliferation of CD4+ and CD8+ T cells, and downregulated the expression of COX2, prostaglandin E synthase, prostaglandin E2, and PD-L1 in CAFs. Conclusion: CAFs promote immune evasion by suppressing the function of CD4+ and CD8+ T cells via their effects on COX2 and PD-L1 in NSCLC. The immunosuppressive function of CAFs could be alleviated by COX2 inhibitors.

Keywords

Acknowledgement

This study was supported by a 2018-grant from The Korean Academy of Tuberculosis and Respiratory Diseases and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020R1A2C2006282).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.  https://doi.org/10.3322/caac.21660
  2. Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol 2006;1:119-50.  https://doi.org/10.1146/annurev.pathol.1.110304.100224
  3. Aran D, Sirota M, Butte AJ. Systematic pan-cancer analysis of tumour purity. Nat Commun 2015;6:8971. 
  4. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423-37.  https://doi.org/10.1038/nm.3394
  5. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer 2016;16:582-98.  https://doi.org/10.1038/nrc.2016.73
  6. Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 2016;30:1002-19.  https://doi.org/10.1101/gad.279737.116
  7. Paulsson J, Micke P. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin Cancer Biol 2014;25:61-8.  https://doi.org/10.1016/j.semcancer.2014.02.006
  8. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71.  https://doi.org/10.1038/nature13954
  9. Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 2018;33:463-79.  https://doi.org/10.1016/j.ccell.2018.01.011
  10. Cho H, Seo Y, Loke KM, Kim SW, Oh SM, Kim JH, et al. Cancer-stimulated CAFs enhance monocyte differentiation and protumoral TAM activation via IL6 and GM-CSF secretion. Clin Cancer Res 2018;24:5407-21.  https://doi.org/10.1158/1078-0432.CCR-18-0125
  11. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 2013;73:3007-18.  https://doi.org/10.1158/0008-5472.CAN-12-4601
  12. Gok Yavuz B, Gunaydin G, Gedik ME, Kosemehmetoglu K, Karakoc D, Ozgur F, et al. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs. Sci Rep 2019;9:3172. 
  13. Zhang J, Zou F, Tang J, Zhang Q, Gong Y, Wang Q, et al. Cyclooxygenase-2-derived prostaglandin E promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor. Circ Res 2013;113:104-14.  https://doi.org/10.1161/CIRCRESAHA.113.301033
  14. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183-8.  https://doi.org/10.1016/0016-5085(94)90246-1
  15. Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999;59:987-90. 
  16. Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761-4. 
  17. Dubois RN. Role of inflammation and inflammatory mediators in colorectal cancer. Trans Am Clin Climatol Assoc 2014;125:358-73. 
  18. Kim SH, Hashimoto Y, Cho SN, Roszik J, Milton DR, Dal F, et al. Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. Pigment Cell Melanoma Res 2016;29:297-308.  https://doi.org/10.1111/pcmr.12455
  19. Shimizu K, Okita R, Saisho S, Maeda AI, Nojima Y, Nakata M. Impact of COX2 inhibitor for regulation of PD-L1 expression in non-small cell lung cancer. Anticancer Res 2018;38:4637-44.  https://doi.org/10.21873/anticanres.12768
  20. Markosyan N, Chen EP, Evans RA, Ndong V, Vonderheide RH, Smyth EM. Mammary carcinoma cell derived cyclooxygenase 2 suppresses tumor immune surveillance by enhancing intratumoral immune checkpoint activity. Breast Cancer Res 2013;15:R75. 
  21. Klein J, Sato A. The HLA system: first of two parts. N Engl J Med 2000;343:702-9.  https://doi.org/10.1056/NEJM200009073431006
  22. Sato N, Maehara N, Goggins M. Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 2004;64:6950-6.  https://doi.org/10.1158/0008-5472.CAN-04-0677
  23. Chen JY, Li CF, Kuo CC, Tsai KK, Hou MF, Hung WC. Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression. Breast Cancer Res 2014;16:410. 
  24. Pinchuk IV, Saada JI, Beswick EJ, Boya G, Qiu SM, Mifflin RC, et al. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology 2008;135:1228-37.  https://doi.org/10.1053/j.gastro.2008.07.016
  25. Su S, Chen J, Yao H, Liu J, Yu S, Lao L, et al. CD10+ GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 2018;172:841-56.  https://doi.org/10.1016/j.cell.2018.01.009
  26. Nordby Y, Richardsen E, Rakaee M, Ness N, Donnem T, Patel HR, et al. High expression of PDGFR-β in prostate cancer stroma is independently associated with clinical and biochemical prostate cancer recurrence. Sci Rep 2017;7:43378. 
  27. Navab R, Strumpf D, Bandarchi B, Zhu CQ, Pintilie M, Ramnarine VR, et al. Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci U S A 2011;108:7160-5.  https://doi.org/10.1073/pnas.1014506108
  28. Su SF, Ho H, Li JH, Wu MF, Wang HC, Yeh HY, et al. DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index. J Clin Invest 2021;131:e139552. 
  29. Hoshino A, Ishii G, Ito T, Aoyagi K, Ohtaki Y, Nagai K, et al. Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res 2011;71:4769-79.  https://doi.org/10.1158/0008-5472.CAN-10-3228
  30. Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res 2012;18:5329-40.  https://doi.org/10.1158/1078-0432.CCR-12-1632
  31. Gorchs L, Fernandez Moro C, Bankhead P, Kern KP, Sadeak I, Meng Q, et al. Human pancreatic carcinoma-associated fibroblasts promote expression of co-inhibitory markers on CD4+ and CD8+ T-cells. Front Immunol 2019;10:847. 
  32. Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov 2019;9:1102-23.  https://doi.org/10.1158/2159-8290.CD-19-0094
  33. Hwang D, Scollard D, Byrne J, Levine E. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst 1998;90:455-60.  https://doi.org/10.1093/jnci/90.6.455
  34. Ogino S, Kirkner GJ, Nosho K, Irahara N, Kure S, Shima K, et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res 2008;14:8221-7.  https://doi.org/10.1158/1078-0432.CCR-08-1841
  35. Edelman MJ, Watson D, Wang X, Morrison C, Kratzke RA, Jewell S, et al. Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy: Cancer and Leukemia Group B Trial 30203. J Clin Oncol 2008;26:848-55. https://doi.org/10.1200/JCO.2007.13.8081