Protective low avidity anti-tumour CD8+ T cells are selectively attenuated by regulatory T cells

Abstract

29Regulatory T cells (Treg) play a major role in the suppression of protective anti-30 tumour T cell responses. In the CT26 BALB/c murine model of colorectal carcinoma, 31Tregs differentially suppress responses to two characterised CD8+ T epitopes, AH1 32 and GSW11, which results in an absence of detectable IFN-γ producing GSW11-33 specific T cells in the spleen and lymph nodes of tumour challenged mice. Activation 34 of GSW11-specific T cells correlates with protection against tumour growth. Here we 35show that GSW11-specific T cells are in fact induced in Treg-replete, CT26-bearing 36 mice, where they make up the majority of tumour infiltrating CD8+ lymphocytes, but 37 exhibit a dysfunctional 'exhausted' phenotype. This dysfunctional phenotype is 38 induced early in the anti-tumour response in draining lymph nodes, spleens and 39 tumours and is significantly more pronounced in GSW11-specific T cells compared to 40 other tumour-specific T cell responses. Depletion of Tregs prior to tumour challenge 41 significantly reduces the induction of exhaustion in GSW11-specific T cells and 42 correlates with altered T cell receptor (TcR) usage. Moreover, the avidity of GSW11-43 specific TcRs that expanded in the absence of Tregs was significantly lower compared 44