Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential

Keywords: Cancer associated fibroblasts (CAF), T-cells, tumour microenvironment (TME), tumour immunity

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population recognized as a key component of the tumour microenvironment (TME). Cancer-associated fibroblasts are known to play an important role in maintaining and remodelling the extracellular matrix (ECM) in the tumour stroma, supporting cancer progression and inhibiting the immune system’s response against cancer cells. This review aims to summarize the immunomodulatory roles of CAFs, particularly focussing on their T-cell suppressive effects.

Cancer-associated fibroblasts have several ways by which they can affect the tumour’s immune microenvironment (TIME). For example, their interactions with macrophages and dendritic cells (DCs) create an immunosuppressive milieu that can indirectly affect T-cell anticancer immunity and enable immune evasion. In addition, a number of recent studies have confirmed CAF-mediated direct suppressive effects on T-cell anticancer capacity through ECM remodelling, promoting the expression of immune checkpoints, cytokine secretion and the release of extracellular vesicles. The consequential impact of CAFs on T-cell function is then reflected in affecting T-cell proliferation and apoptosis, migration and infiltration, differentiation and exhaustion. Emerging evidence highlights the existence of specific CAF subsets with distinct capabilities to modulate the immune landscape of TME in various cancers, suggesting the possibility of their exploitation as possible prognostic biomarkers and therapeutic targets.

Downloads

Download data is not yet available.

References

1. Virchow R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI – atheromatous affection of arteries. 1858. Nutr Rev. 1989;47:23–5. doi: 10.1111/j.1753-4887.1989.tb02747.x

2. Tarin D, Croft CB. Ultrastructural features of wound healing in mouse skin. J Anat. 1969;105:189–90.

3. Plikus M V, Wang X, Sinha S, Forte E, Thompson SM, Herzog EL, et al. Fibroblasts: origins, definitions, and functions in health and disease. Cell. 2021;184:3852–72. doi: 10.1016/j.cell.2021.06.024

4. Schor SL. Fibroblast subpopulations as accelerators of tumor progression: the role of migration stimulating factor. EXS. 1995;74:273–96. doi: 10.1007/978-3-0348-9070-0_14

5. Herrero A, Knetemann E, Mannaerts I. Review: challenges of in vitro CAF modelling in liver cancers. Cancers. 2021;13: 5914. doi: 10.3390/cancers13235914

6. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6: 392–401. doi: 10.1038/nrc1877

7. Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, et al. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 2019;38: 4887–901. doi: 10.1038/s41388-019-0765-y

8. Han C, Liu T, Yin R. Biomarkers for cancer-associated fibroblasts. Biomark Res. 2020;8:64. doi: 10.1186/s40364-020-00245-w

9. Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: cancer-associated fibroblasts and their markers. Int J Cancer. 2020;146:895–905. doi: 10.1002/ijc.32193

10. Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021;18:792–804. doi: 10.1038/s41571-021-00546-5

11. Ping Q, Yan R, Cheng X, Wang W, Zhong Y, Hou Z, et al. Cancer-associated fibroblasts: overview, progress, challenges, and directions. Cancer Gene Ther. 2021;28:984–99. doi: 10.1038/s41417-021-00318-4

12. Yang D, Liu J, Qian H, Zhuang Q. Cancer-associated fibroblasts: from basic science to anticancer therapy. Exp Mol Med. 2023;55:1322–32. doi: 10.1038/s12276-023-01013-0

13. Kennel KB, Bozlar M, De Valk AF, Greten FR. Cancer-Associated Fibroblasts in Inflammation and Antitumor Immunity. Clin Cancer Res. 2023;29:1009–16. doi: 10.1158/1078-0432.CCR-22-1031

14. Erez N, Truitt M, Olson P, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell. 2010;17:135–47. doi: 10.1016/j.ccr.2009.12.041

15. Ren G, Zhao X, Wang Y, Zhang X, Chen X, Xu C, et al. CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα. Cell Stem Cell. 2012;11:812–24. doi: 10.1016/j.stem.2012.08.013

16. Jia XH, Du Y, Mao D, Wang ZL, He ZQ, Qiu JD, et al. Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages. Oncotarget. 2015;6:26018–28. doi: 10.18632/oncotarget.4658

17. 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. doi: 10.1038/s41598-019-39553-z

18. Cohen N, Shani O, Raz Y, Sharon Y, Hoffman D, Abramovitz L, et al. Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1. Oncogene. 2017;36:4457–68. doi: 10.1038/onc.2017.65

19. Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012;318:154–61. doi: 10.1016/j.canlet.2011.12.020

20. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M, et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci U S A. 2009;106:20847–52. doi: 10.1073/pnas.0906481106

21. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20:131. doi: 10.1186/s12943-021-01428-1

22. Suciu-Foca N, Berloco P, Cortesini R. Tolerogenic dendritic cells in cancer, transplantation, and autoimmune diseases. Hum Immunol. 2009;70:277–80. doi: 10.1016/j.humimm.2009.03.003

23. Cheng J t, Deng Y n, Yi H m, Wang G y, Fu B s, Chen W j, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis. 2016;5:e198. doi: 10.1038/oncsis.2016.7

24. Koppensteiner L, Mathieson L, OíConnor RA, Akram AR. Cancer associated fibroblasts – an impediment to effective anti-cancer T cell immunity. Front Immunol. 2022;13:887380. doi: 10.3389/fimmu.2022.887380

25. Takahashi H, Sakakura K, Kawabata-Iwakawa R, Rokudai S, Toyoda M, Nishiyama M, et al. Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer Immunol Immunother. 2015;64:1407–17. doi: 10.1007/s00262-015-1742-0

26. Gorchs L, Hellevik T, Bruun JA, Camilio KA, Al-Saad S, Stuge TB, et al. Cancer-associated fibroblasts from lung tumors maintain their immunosuppressive abilities after high-dose irradiation. Front Oncol. 2015;5:87. doi: 10.3389/fonc.2015.00087

27. Gorchs L, Fernández 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. doi: 10.3389/fimmu.2019.00847

28. Abuwarwar MH, Baker AT, Harding J, Payne NL, Nagy A, Knoblich K, et al. In Vitro Suppression of T cell proliferation is a conserved function of primary and immortalized human cancer-associated fibroblasts. Int J Mol Sci. 2021;22:1827. doi: 10.3390/ijms22041827

29. Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Investig. 2012;122:899–910. doi: 10.1172/JCI45817

30. Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, et al. NOX4 Inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res. 2020;80:1846–60. doi: 10.1158/0008-5472.CAN-19-3158

31. Érsek B, Silló P, Cakir U, Molnár V, Bencsik A, Mayer B, et al. Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity. Cell Mol Life Sci. 2021;78:661–73. doi: 10.1007/s00018-020-03517-8

32. Kato T, Noma K, Ohara T, Kashima H, Katsura Y, Sato H, et al. Cancer-associated fibroblasts affect intratumoral CD8(+) and FoxP3(+) T cells Via IL6 in the tumor microenvironment. Clin Cancer Res. 2018;24:4820–33. doi: 10.1158/1078-0432.CCR-18-0205

33. Brown FD, Sen DR, LaFleur MW, Godec J, Lukacs-Kornek V, Schildberg FA, et al. Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling. Nat Immunol. 2019;20: 1668–80. doi: 10.1038/s41590-019-0515-x

34. Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020;10:1330–51. doi: 10.1158/2159-8290.CD-19-1384

35. Huang H, Wang Z, Zhang Y, Pradhan RN, Ganguly D, Chandra R, et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell. 2022;40:656–73.e7. doi: 10.1016/j.ccell.2022.04.011

36. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med. 2011;208:469–78. doi: 10.1084/jem.20101876

37. Huang TX, Tan XY, Huang HS, Li YT, Liu BL, Liu KS, et al. Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut. 2022;71:333–44. doi: 10.1136/gutjnl-2020-322924

38. Allaoui R, Bergenfelz C, Mohlin S, Hagerling C, Salari K, Werb Z, et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat Commun. 2016;7:13050. doi: 10.1038/ncomms13050

39. Gunaydin G. CAFs Interacting with TAMs in tumor microenvironment to enhance tumorigenesis and immune evasion. Front Oncol. 2021;11:668349. doi: 10.3389/fonc.2021.668349

40. Takahashi H, Sakakura K, Kudo T, Toyoda M, Kaira K, Oyama T, et al. Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages. Oncotarget. 2017;8:8633–47. doi: 10.18632/oncotarget.14374

41. Takahashi H, Rokudai S, Kawabata-Iwakawa R, Sakakura K, Oyama T, Nishiyama M, et al. AKT3 is a novel regulator of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancers. 2021;13: 1233. doi: 10.3390/cancers13061233

42. Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD. Cancer-associated fibroblasts induce antigen-specific deletion of CD8+T Cells to protect tumour cells. Nat Commun. 2018;9:948. doi: 10.1038/s41467-018-03347-0

43. Zhang H, Jiang R, Zhou J, Wang J, Xu Y, Zhang H, et al. CTL Attenuation regulated by PS1 in cancer-associated fibroblast. Front Immunol. 2020;11:999. doi: 10.3389/fimmu.2020.00999

44. Milosevic V, Kopecka J, Salaroglio IC, Libener R, Napoli F, Izzo S, et al. Wnt/IL- 1β/IL -8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5. Int J Cancer. 2019;146:192–207. doi: 10.1002/ijc.32419

45. Kiss M, Vande Walle L, Saavedra PH V, Lebegge E, Van Damme H, Murgaski A, et al. IL1β promotes immune suppression in the tumor microenvironment independent of the inflammasome and gasdermin D. Cancer Immunol Re. 2021;9:309–23. doi: 10.1158/2326-6066.CIR-20-0431

46. Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac K, Woodruff MC, et al. FAP Delineates heterogeneous and functionally divergent stromal cells in immune-excluded breast tumors. Cancer Immunol Res. 2018;6:1472–85. doi: 10.1158/2326-6066.CIR-18-0098

47. Mei J, Ma J, Xu Y, Wang Y, Hu M, Ma F, et al. Cinnamaldehyde treatment of prostate cancer-associated fibroblasts prevents their inhibitory effect on t cells through toll-like receptor 4. Drug Design Dev Ther. 2020;14:3363–72. doi: 10.2147/DDDT.S241410

48. Chen M, Xiang R, Wen Y, Xu G, Wang C, Luo S, et al. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts. Sci Rep. 2015;5:14421. doi: 10.1038/srep14421

49. Akhand SS, Liu Z, Purdy SC, Abdullah A, Lin H, Cresswell GM, et al. Pharmacologic inhibition of FGFR modulates the metastatic immune microenvironment and promotes response to immune checkpoint blockade. Cancer Immunol Res. 2020;8:1542–3. doi: 10.1158/2326-6066.CIR-20-0235

50. Matloubian M, David A, Engel S, Ryan JE, Cyster JG. A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat Immunol. 2000;1:298–304. doi: 10.1038/79738

51. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8. doi: 10.1038/nature25501

52. Desbois M, Udyavar AR, Ryner L, Kozlowski C, Guan Y, Dürrbaum M, et al. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat Commun. 2020;11:5583. doi: 10.1038/s41467-020-19408-2

53. Lee B, Lee S-H, Shin K. Crosstalk between fibroblasts and T cells in immune networks. Front Immunol. 2022;13:1103823. doi: 10.3389/fimmu.2022.1103823

54. ChirivÏ M, Maiullari F, Milan M, Presutti D, Cordiglieri C, Crosti M, et al. Tumor extracellular matrix stiffness promptly modulates the phenotype and gene expression of infiltrating T lymphocytes. Int J Mol Sci. 2021;22:5862. doi: 10.3390/ijms22115862

55. Mhaidly R, Mechta-Grigoriou F. Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer. Immunol Rev. 2021;302:259–72. doi: 10.1111/imr.12978

56. Kondo Y, Suzuki S, Takahara T, Ono S, Goto M, Miyabe S, et al. Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma. Cancer Sci. 2021;112:4037–49. doi: 10.1111/cas.15081

57. Li D, Schaub N, Guerin TM, Bapiro TE, Richards FM, Chen V, et al. T cell-mediated antitumor immunity cooperatively induced By TGFβR1 antagonism and gemcitabine counteracts reformation of the stromal barrier in pancreatic cancer. Mol Cancer Ther. 2021;20:1926–40. doi: 10.1158/1535-7163.MCT-20-0620

58. Sakai T, Aokage K, Neri S, Nakamura H, Nomura S, Tane K, et al. Link between tumor-promoting fibrous microenvironment and an immunosuppressive microenvironment in stage I lung adenocarcinoma. Lung Cancer. 2018;126:64–71. doi: 10.1016/j.lungcan.2018.10.021

59. Thomas DA, Massagué J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369–80. doi: 10.1016/j.ccr.2005.10.012

60. McKarns SC, Schwartz RH, Kaminski NE. Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol. 2004;172:4275–84. doi: 10.4049/jimmunol.172.7.4275

61. Shintani Y, Fujiwara A, Kimura T, Kawamura T, Funaki S, Minami M, et al. IL-6 Secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial-mesenchymal transition signaling. J Thorac Oncol. 2016;11:1482–92. doi: 10.1016/j.jtho.2016.05.025

62. Karakasheva TA, Lin EW, Tang Q, Qiao E, Waldron TJ, Soni M, et al. IL-6 mediates cross-talk between tumor cells and activated fibroblasts in the tumor microenvironment. Cancer Res. 2018;78:4957–70. doi: 10.1158/0008-5472.CAN-17-2268

63. Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007;8:1255–65. doi: 10.1038/ni1513

64. Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 2018;78:5011–22. doi: 10.1158/0008-5472.CAN-18-0118

65. Barnas JL, Simpson-Abelson MR, Brooks SP, Kelleher RJJ, Bankert RB. Reciprocal functional modulation of the activation of T lymphocytes and fibroblasts derived from human solid tumors. J Immunol. 2010;185:2681–92. doi: 10.4049/jimmunol.1000896

66. Li R, Wei F, Yu J, Li H, Ren X, Hao X. IDO inhibits T-cell function through suppressing Vav1 expression and activation. Cancer Biol Ther. 2009; 8:1402–8. doi: 10.4161/cbt.8.14.8882

67. Li Q, Harden JL, Anderson CD, Egilmez NK. Tolerogenic phenotype of IFN-γ-induced IDO+ dendritic cells is maintained via an autocrine IDO-Kynurenine/AhR-IDO loop. J Immunol. 2016;197:962–70. doi: 10.4049/jimmunol.1502615

68. Liu H, Liu L, Liu K, Bizargity P, Hancock WW, Visner GA. Reduced cytotoxic function of effector CD8+ T cells is responsible for indoleamine 2,3-dioxygenase-dependent immune suppression. J Immunol. 2009;183:1022–31. doi: 10.4049/jimmunol.0900408

69. Kim DS, Jang IK, Lee MW, Ko YJ, Lee DH, Lee JW, et al. Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ. EBioMedicine. 2018;28:261–73. doi: 10.1016/j.ebiom.2018.01.002

70. Meireson A, Devos M, Brochez L. IDO expression in cancer: different compartment, different functionality? Front Immunol. 2020;11:531491. doi: 10.3389/fimmu.2020.531491

71. Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Sosman JA, et al. Immunosuppressive IDO in cancer: mechanisms of action, animal models, and targeting strategies. Front Immunol. 2020;11:1185. doi: 10.3389/fimmu.2020.01185

72. Nandre R, Verma V, Gaur P, Patil V, Yang X, Ramlaoui Z, et al. IDO vaccine ablates immune-suppressive myeloid populations and enhances antitumor effects independent of tumor cell IDO status. Cancer Immunol Res. 2022;10:571–80. doi: 10.1158/2326-6066.CIR-21-0457

73. Hu Y, Recouvreux MS, Haro M, Taylan E, Taylor-Harding B, Walts AE, et al. INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer. NPJ Precis Oncol. 2024;8:35. doi: 10.1038/s41698-024-00523-y

74. Dou D, Ren X, Han M, Xu X, Ge X, Gu Y, et al. Cancer-associated fibroblasts-derived exosomes suppress immune cell function in breast cancer via the miR-92/PD-L1 pathway. Front Immunol. 2020;11:2026. doi: 10.3389/fimmu.2020.02026

75. O’Connor RA, Chauhan V, Mathieson L, Titmarsh H, Koppensteiner L, Young I, et al. T cells drive negative feedback mechanisms in cancer associated fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer. Oncoimmunology. 2021;10:1940675. doi: 10.1080/2162402X.2021.1940675

76. Jiang X, Wu X, Xiao Y, Wang P, Zheng J, Wu X, et al. The ectonucleotidases CD39 and CD73 on T cells: the new pillar of hematological malignancy. Front Immunol. 2023;14:1110325. doi: 10.3389/fimmu.2023.1110325

77. Koppensteiner L, Mathieson L, Pattle S, Dorward DA, OíConnor R, Akram AR. Location of CD39(+) T cell subpopulations within tumors predict differential outcomes in non-small cell lung cancer. J Immunother Cancer. 2023;11:e006770. doi: 10.1136/jitc-2023-006770

78. Zhu C, Sakuishi K, Xiao S, Sun Z, Zaghouani S, Gu G, et al. An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun. 2015;6:1–11. doi: 10.1038/ncomms7072

79. Morishima N, Owaki T, Asakawa M, Kamiya S, Mizuguchi J, Yoshimoto T. Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27. J Immunol. 2005;175:1686–93. doi: 10.4049/jimmunol.175.3.1686

80. 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.e10. doi: 10.1016/j.ccell.2018.01.011

81. 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. doi: 10.1158/2159-8290.CD-19-0094

82. Dominguez CX, Müller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 2020;10:232–53. doi: 10.1158/2159-8290.CD-19-064

83. Kanzaki R, Pietras K. Heterogeneity of cancer-associated fibroblasts: opportunities for precision medicine. Cancer Sci. 2020;111:2708–17. doi: 10.1111/cas.14537

84. Pellinen T, Paavolainen L, MartÌn-BernabÈ A, Papatella Araujo R, Strell C, Mezheyeuski A, et al. Fibroblast subsets in non-small cell lung cancer: associations with survival, mutations, and immune features. J Natl Cancer Inst. 2023;115:71–82. doi: 10.1093/jnci/djac178

85. Givel AM, Kieffer Y, Scholer-Dahirel A, Sirven P, Cardon M, Pelon F, et al. miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat Commun. 2018;9:1056. doi: 10.1038/s41467-018-03348-z

86. Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol. 2015;16:850–8. doi: 10.1038/ni.3201

87. Decalf J, Tarbell K V, Casrouge A, Price JD, Linder G, Mottez E, et al. Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies. EMBO Mol Med. 2016;8:679–83. doi: 10.15252/emmm.201506145

88. Coto-Llerena M, Ercan C, Kancherla V, Taha-Mehlitz S, Eppenberger-Castori S, Soysal SD, et al. High expression of FAP in colorectal cancer is associated with angiogenesis and immunoregulation processes. Front Oncol. 2020;10:979. doi: 10.3389/fonc.2020.00979

89. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7. doi: 10.1016/s1074-7613(00)80165-x

90. Proudfoot AEI. The biological relevance of chemokine-proteoglycan interactions. Biochem Soc Trans. 2006;34:422–6. doi: 10.1042/BST0340422

91. Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110:20212–7. doi: 10.1073/pnas.1320318110

92. Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014;2:187–93. doi: 10.1158/2326-6066.CIR-14-0002

93. Blair AB, Kim VM, Muth ST, Saung MT, Lokker N, Blouw B, et al. Dissecting the stromal signaling and regulation of myeloid cells and memory effector T cells in pancreatic cancer. Clin Cancer Res. 2019;25:5351–63. doi: 10.1158/1078-0432.CCR-18-4192

94. Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26:878–85. doi: 10.1038/s41591-020-0880-x

95. Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96. doi: 10.1084/jem.20162024

96. Chen QY, Li YN, Wang XY, Zhang X, Hu Y, Li L, et al. Tumor fibroblast-derived FGF2 regulates expression of SPRY1 in esophageal tumor-infiltrating T cells and plays a role in T-cell exhaustion. Cancer Res. 2020;80:5583–96. doi: 10.1158/0008-5472.CAN-20-1542

97. AlQudah M, Hale TM, Czubryt MP. Targeting the renin-angiotensin-aldosterone system in fibrosis. Matrix Biol. 2020;91–92:92–108. doi: 10.1016/j.matbio.2020.04.005

98. Magagna I, Gourdin N, Kieffer Y, Licaj M, Mhaidly R, Andre P, et al. CD73-Mediated immunosuppression is linked to a specific fibroblast population that paves the way for new therapy in breast cancer. Cancers. 2021;13:5878. doi: 10.3390/cancers13235878

99. Grout JA, Sirven P, Leader AM, Maskey S, Hector E, Puisieux I, et al. Spatial positioning and matrix programs of cancer-associated fibroblasts promote T-cell exclusion in human lung tumors. Cancer Discov. 2022;12:2606–25. doi: 10.1158/2159-8290.CD-21-1714

100. Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021;53:1334–47. doi: 10.1038/s41588-021-00911-1

101. Obradovic AZ, Dallos MC, Zahurak ML, Partin AW, Schaeffer EM, Ross AE, et al. T-cell infiltration and adaptive Treg resistance in response to androgen deprivation with or without vaccination in localized prostate cancer. Clin Cancer Res. 2020;26:3182–92. doi: 10.1158/1078-0432.CCR-19-3372

102. Cords L, Engler S, Haberecker M, Rüschoff JH, Moch H, de Souza N, et al. Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer. Cancer Cell. 2024;42:396–412. doi: 10.1016/j.ccell.2023.12.021

103. Davidson G, Helleux A, Vano YA, Lindner V, Fattori A, Cerciat M, et al. Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear cell renal cell carcinoma. Cancer Res. 2023;83:2952–69. doi: 10.1158/0008-5472.CAN-22-3034

104. Ying F, Chan MSM, Lee TKW. Cancer-associated fibroblasts in hepatocellular carcinoma and cholangiocarcinoma. Cell Mol Gastroenterol Hepatol. 2023;15:985–99. doi: 10.1016/j.jcmgh.2023.01.006
Published
2024-05-24
How to Cite
Milosevic V., & Östman A. (2024). Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential. Upsala Journal of Medical Sciences, 129(S1), e10710. https://doi.org/10.48101/ujms.v129.10710