Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients.
Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated.
CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors.
Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.
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Patel N, Benipal B. Incidence of cholangiocarcinoma in the USA from 2001 to 2015: a US Cancer statistics analysis of 50 states. Cureus. 2019;11:e3962.
Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383:2168–79.
Gupta A, Dixon E. Epidemiology and risk factors: intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr. 2017;6:101–4.
DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245:755–62.
Goldaracena N, Gorgen A, Sapisochin G. Current status of liver transplantation for cholangiocarcinoma. Liver Transplant. 2018;24:294–303.
Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657–69.
Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014;149:565–74.
Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.
Mahale J, Smagurauskaite G, Brown K, Thomas A, Howells LM. The role of stromal fibroblasts in lung carcinogenesis: a target for chemoprevention? Int J Cancer. 2016;138:30–44.
Yoshida T, Ishii G, Goto K, Neri S, Hashimoto H, Yoh K, et al. Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clin Cancer Res. 2015;21:642–51.
Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.
Harper J, Sainson RC. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol. 2014;25:69–77.
Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS ONE. 2009;4:e7965.
van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439–46.
Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.
Volonte D, Vyas AR, Chen C, Dacic S, Stabile LP, Kurland BF, et al. Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence. J Biol Chem. 2018;293:1794–809.
Yamao T, Yamashita YI, Yamamura K, Nakao Y, Tsukamoto M, Nakagawa S, et al. Cellular senescence, represented by expression of caveolin-1, in cancer-associated fibroblasts promotes tumor invasion in pancreatic cancer. Ann Surg Oncol. 2019;26:1552–9.
Mercier I, Casimiro MC, Wang C, Rosenberg AL, Quong J, Minkeu A, et al. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: implications for the response to hormonal therapy. Cancer Biol Ther. 2008;7:1212–25.
Capparelli C, Guido C, Whitaker-Menezes D, Bonuccelli G, Balliet R, Pestell TG, et al. Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle (Georget, Tex). 2012;11:2285–302.
Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66.
Ma C, Dong X. Colorectal cancer-derived Foxp3(+) IL-17(+) T cells suppress tumour-specific CD8+ T cells. Scand J Immunol. 2011;74:47–51.
Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–4.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.
Arigami T, Uenosono Y, Ishigami S, Matsushita D, Hirahara T, Yanagita S, et al. Decreased density of CD3+ tumor-infiltrating lymphocytes during gastric cancer progression. J Gastroenterol Hepatol. 2014;29:1435–41.
Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, et al. CD8+ cytotoxic Tcell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. 2011;130:645–55.
Teng F, Mu D, Meng X, Kong L, Zhu H, Liu S, et al. Tumor infiltrating lymphocytes (TILs) before and after neoadjuvant chemoradiotherapy and its clinical utility for rectal cancer. Am J Cancer Res. 2015;5:2064–74.
Gu FM, Gao Q, Shi GM, Zhang X, Wang J, Jiang JH, et al. Intratumoral IL-17+ cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2012;19:2506–14.
Asahi Y, Hatanaka KC, Hatanaka Y, Kamiyama T, Orimo T, Shimada S, et al. Prognostic impact of CD8+ T cell distribution and its association with the HLA class I expression in intrahepatic cholangiocarcinoma. Surg Today. 2020;50:931–40.
Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 2015;75:2139–45.
Yagi T, Baba Y, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, et al. PD-L1 expression, tumor-infiltrating lymphocytes, and clinical outcome in patients with surgically resected esophageal cancer. Ann Surg. 2019;269:471–8.
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.
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.
Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem. 1998;273:5419–22.
Shan-Wei W, Kan-Lun X, Shu-Qin R, Li-Li Z, Li-Rong C. Overexpression of caveolin-1 in cancer-associated fibroblasts predicts good outcome in breast cancer. Breast Care. 2012;7:477–83.
Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, et al. Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle. 2012;11:1108–17.
Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, et al. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010;9:3534–51.
Shen XJ, Zhang H, Tang GS, Wang XD, Zheng R, Wang Y, et al. Caveolin-1 is a modulator of fibroblast activation and a potential biomarker for gastric cancer. Int J Biol Sci. 2015;11:370–9.
Di Vizio D, Morello M, Sotgia F, Pestell RG, Freeman MR, Lisanti MP. An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation. Cell Cycle. 2009;8:2420–4.
Martinez-Outschoorn UE, Lisanti MP, Sotgia F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin Cancer Biol. 2014;25:47–60.
Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, et al. Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle. 2011;10:1794–809.
Goetz JG, Minguet S, Navarro-Lérida I, Lazcano JJ, Samaniego R, Calvo E, et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011;146:148–63.
Krtolica A, Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol. 2002;34:1401–14.
Volonte D, Zou H, Bartholomew JN, Liu Z, Morel PA, Galbiati F. Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6). J Biol Chem. 2015;290:4202–14.
Nolz JC. Molecular mechanisms of CD8(+) T cell trafficking and localization. Cell Mol Life Sci. 2015;72:2461–73.
Kitano Y, Okabe H, Yamashita YI, Nakagawa S, Saito Y, Umezaki N, et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer. 2018;118:171–80.
Feig C, Jones JO, Kraman M, Wells RJ, 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 USA. 2013;110:20212–7.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.
Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res. 2016;76:4124–35.
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Lan, C., Kitano, Y., Yamashita, Yi. et al. Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01569-6