Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma

• Published in: British journal of cancer Vol. 126; no. 2; pp. 219 - 227
• Main Authors: Lan, Chuan, Kitano, Yuki, Yamashita, Yo-ichi, Yamao, Takanobu, Kajiyama, Kiyoshi, Yoshizumi, Tomoharu, Fukuzawa, Kengo, Sugimachi, Keishi, Ikeda, Yasuharu, Takamori, Hiroshi, Miyanari, Nobutomo, Hirota, Masahiko, Baba, Hideo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2022; Nature Publishing Group
• Subjects: 692/308/53; 692/4028/67/1504/1610; 692/4028/67/327; Aged; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Bile Duct Neoplasms - immunology; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Caveolin; Caveolin 1 - metabolism; Caveolin-1; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cellular Senescence; Cholangiocarcinoma; Cholangiocarcinoma - immunology; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Drug Resistance; Epidemiology; Female; Fibroblasts; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Foxp3 protein; Humans; Immunohistochemistry; Lymph nodes; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical prognosis; Metastases; Molecular Medicine; Multivariate analysis; Oncology; PD-L1 protein; Prognosis; Senescence; Survival Rate; Therapeutic targets; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-021-01569-6

Background 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. Methods 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. Results 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. Conclusion 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.