Abstract
Objective: Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression.Methods: Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their function in vivo and in vitro after silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated.Results: PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models (p < 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1β was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing (p < 0.05), which was regulated by the WNT/β-catenin pathway. It was also showed that high expression of IL-1β in CAFs inhibits CTL penetration significantly (p < 0.05).Conclusion: Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/β-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies.
Highlights
Immunotherapy is recognized as an important therapeutic strategy for cancers and attracts more and more attention
We started our study from a candidate pool with nine differential expressed genes (>8-fold) related to cytotoxic T lymphocytes (CTLs) penetration regulation, which were obtained from microarray assay with fibroblast samples of 10 normal human ovaries and 83 ovarian tumors
These genes were ALDCA, ACKR3, BACE2, ATP5C1, ARF4, CCT3, CKAP4, ATP1B1, and ARPC3, and they were all significantly associated with lower CD8+ T cell counts in high-grade serous ovarian carcinoma (HGSC) and higher CD8+ T cell numbers in cancer-associated fibroblasts (CAFs) when compared with normal fibroblasts
Summary
Immunotherapy is recognized as an important therapeutic strategy for cancers and attracts more and more attention. High levels of intratumoral T cells are strongly and consistently correlated with patient survival in multiple cancer types, including high-grade serous ovarian carcinoma (HGSC) and pancreatic ductal adenocarcinoma [1, 2]. CAFs Cause CTL Attenuation antibodies, such as those against programmed cell death-1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4), have shown remarkable efficacy in certain cancer types such as melanoma and non-small-cell lung carcinoma [3, 4], limited therapeutic benefit has been observed in other types of cancers such as colorectal cancer, ovarian cancer, and pancreatic ductal adenocarcinoma. A recent clinical trial of PD-L1 showed limited benefit for ovarian cancer patients, with only 1 out of 17 patients having a partial response [5]. Immunotherapy has, far, shown limited efficiency in pancreatic ductal adenocarcinoma. The difficulty of inducing an effective antitumor immune response largely stems from the highly immunosuppressive microenvironment present in these tumors [6]
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