Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β

Adoptive T cell therapy with T cells expressing affinity-enhanced TCRs has shown promising results in phase 1/2 clinical trials for solid and hematological tumors. However, depth and durability of responses to adoptive T cell therapy can suffer from an inhibitory tumor microenvironment. A common immune-suppressive agent is TGF-beta, which is secreted by tumor cells and cells recruited to the tumor. We investigated whether human T cells could be engineered to be resistant to inhibition by TGF-beta. Truncating the intracellular signaling domain from TGF-beta receptor (TGF beta R) II produces a dominant-negative receptor (dnTGF beta RII) that dimerizes with endogenous TGF beta RI to form a receptor that can bind TGF-beta but cannot signal. We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02-restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)(157-165)/L-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1(c259)) and melanoma Ag gene A10(254-262) (TCR: ADP-A2M10, formerly melanoma Ag gene A10(c796)). In this article, we show that exogenous TGF-beta inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGF beta RII (e.g., GSK3845097). TGF-beta isoforms and a panel of TGF-beta-associated genes are overexpressed in a range of cancer indications in which NY-ESO-1 is commonly expressed, particularly in synovial sarcoma. As an example, immunohistochemistry/RNAscope identified TGF-beta-positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-gamma in a non-small cell lung cancer setting. Coexpression of dnTGF beta RII may therefore improve the efficacy of TCR-transduced T cells.

Automated summary

Coexpressing dnTGF-beta RII with high-affinity TCRs can alleviate the inhibitory effect of exogenous TGF-beta on human T cells expressing the TCRs.