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Translational Therapeutics

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

Abstract

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.

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Fig. 1: Representative images of immunohistochemical staining for Caveolin-1 (CAV1), CD8, Foxp3 and PD-L1.
Fig. 2: The Kaplan–Meier curves for survival analysis in patients with intrahepatic cholangiocarcinoma according to CAV1 expression in CAFs.
Fig. 3: The relationship between CAV1 expression in CAFs in ICC and the OS.
Fig. 4: Correlation analysis between CAV1 expression in CAFs and CD8+ TILs, Foxp3+ TILs, and PD-L1 expression in cancer cells.
Fig. 5: The Kaplan–Meier curves for OS analysis in patients with intrahepatic cholangiocarcinoma according to CD8+ and Foxp3+ TILs count.

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KY and YT contributed to the immunostaining of samples. LC, KY and YY contributed to the evaluation of immunostaining. LC and YY contributed to the statistical analyses. YY, KK, YT, FK, SK, IY, TH, MN, HM and BH contributed to obtaining surgical specimens. LC and YY contributed to writing a paper. BH contributed to revising a paper. All authors approved the final version of the manuscript.

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Correspondence to Hideo Baba.

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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

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