Transplantation of the MSLN-deficient Thymus Generates MSLN Epitope Reactive T Cells to Attenuate Tumor Progression.

Abstract

The development of mesothelin (MSLN) epitope reactive T cells is observed in mice that are immunized with the MSLN vaccine. Engineered T cells expressing MSLN-reactive high-affinity TCR exhibit extraordinary therapeutic effects for invasive pancreatic ductal adenocarcinoma in a mouse model. However, the generation of MSLN-reactive T cells through the introduction of MSLN-deficient thymus and the transplantation of the latter as a cure for cancer treatment have not been tested to date. In the present study, the expression of MSLN was mainly identified in medullary thymic epithelial cells (mTECs) but not in hematopoietic cells, cortical thymic epithelial cells (cTECs), endothelial cells, or fibroblast cells in the thymus. The increasement of activated T cells was observed in MSLN-expressing tumors from MSLN-deficient mice, indicating that MSLN-reactive T cells had developed. Finally, in an AOM-DSS-induced mouse model of colorectal cancer (CRC), transplantation of MSLN-deficient thymus repressed the progression of CRC, accompanied by an increased number of IFNγ-expressing T lymphocytes in the tumors. The data from this study demonstrated that ectopic transplantation of MSLN-deficient thymus induced MSLN-specific antitumor responses to MSLN-expressing tumors, and thus attenuated tumor progression.