TIM-4 increases the proportion of CD4+CD25+FOXP3+ regulatory T cells in the pancreatic ductal adenocarcinoma microenvironment by inhibiting IL-6 secretion.

ABSTRACT

BACKGROUND: Currently, creating more effector T cells and augmenting their functions is a focal point in pancreatic ductal adenocarcinoma (PDAC) treatment research. T cell immunoglobulin domain and mucin domain molecule 4 (TIM-4), known for promoting cancer progression in various malignancies, is implicated in the suppressive immune microenvironment of tumors. Analyzing of the role of TIM-4 in the immune regulation of PDAC can offer novel insights for immune therapy. METHODS: We analyzed the TIM-4 expression in tumor specimens from PDAC patients. Meanwhile, multiple fluorescent immunohistochemical staining was used to study the distribution characteristics of TIM-4, and through tissue microarrays, we explored its correlation with patient prognosis. The influence of TIM-4 overexpression on cell function was analyzed using RNA-seq. Flow cytometry and ELISA were used for verification. Finally, the relationship between TIM-4 and T lymphocytes was analyzed by tissue microarray, and the impacts of TIM-4 on T cell subsets were observed by cell coculture technology and a mouse pancreatic cancer in situ model. RESULTS: In PDAC, TIM-4 is mainly expressed in tumor cells and negatively correlated with patient prognosis. TIM-4 influences the differentiation of Treg by inhibiting IL-6 secretion in pancreatic cancer cells and facilitates the proliferation of pancreatic cancer in mice. Additionally, the mechanism may be through the CD8+ effector T cells (CD8+Tc). CONCLUSION: TIM-4 has the potential to be an immunotherapeutic target or to improve the efficacy of chemotherapy for PDAC.