Journal Article

FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18.2-targeted CAR-T against pancreatic cancer

Wang, Peng, Sun, Yansha, Zhou, Min, Shi, Bizhi, Li, Zonghai, Liu, Yifan, Li, Songling, Dong, Yiwei, Sun, Ruixin, Jiang, Hua

2023

Overview

Purpose The claudin 18.2 (CLDN18.2) antigen is frequently expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). Although CLDN18.2-targeted CAR-T cells demonstrated some therapeutic efficacy in PDAC patients, further improvement is needed. One of the major obstacles might be the abundant cancer-associated fibroblasts (CAFs) in the PDAC tumor microenvironment (TME). Targeting fibroblast activation protein (FAP), a vital characteristic of CAFs provides a potential way to overcome this obstacle. In this study, we explored the combined antitumor activity of FAP-targeted and CLDN18.2-targeted CAR-T cells against PDAC. Methods Novel FAP-targeted CAR-T cells were developed. Sequential treatment of FAP-targeted and CLDN18.2-targeted CAR-T cells as well as the corresponding mechanism were explored in immunocompetent mouse models of PDAC. Results The results indicated that the priorly FAP-targeted CAR-T cells infusion could significantly eliminate CAFs and enhance the anti-PDAC efficacy of subsequently CLDN18.2-targeted CAR-T cells in vivo. Interestingly, we observed that FAP-targeted CAR-T cells could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) and promote the survival of CD8 + T cells and CAR-T cells in tumor tissue. Conclusion In summary, our finding demonstrated that FAP-targeted CAR-T cells could increase the antitumor activities of sequential CAR-T therapy via remodeling TME, at least partially through inhibiting MDSCs recruitment. Sequential infusion of FAP-targeted and CLDN18.2-targeted CAR-T cells might be a feasible approach to enhance the clinical outcome of PDAC.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Animal models / Animals / Antibodies / Antigens / Antitumor activity / Biomedical and Life Sciences / Biomedicine / Breast cancer / Carcinoma, Pancreatic Ductal - therapy / Care and treatment / CD8 antigen / CD8-Positive T-Lymphocytes / Cell / Cell Line, Tumor / Cells / Fibroblast activation protein / Fibroblasts / Flow cytometry / Health aspects / Humans / Immunotherapy / Laboratory animals / Lymphocytes / Lymphocytes T / Medical prognosis / Medicine/Public Health / Mice / Myeloid-Derived Suppressor Cells - metabolism / Packaging / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - therapy / Proteases / Proteins / Receptors, Chimeric Antigen - metabolism / Serine Endopeptidases - metabolism / Suppressor cells / tissue and gene therapy / Tumor Microenvironment