T cell receptor revision as a novel mechanism of action of immune checkpoint blockade

Abstract

Abstract Background Immune checkpoint blockade (ICB) is a promising therapy prescribed to combat tumors. However, acquired resistance to ICB highlights the need for a better understanding of ICB mechanisms. Analysis of T cell receptor (TCR) sequences in individuals before and after ICB showed that a distinct TCR repertoire was observed following ICB, suggesting that T cells with novel specificities contribute to tumor clearance. While the source of these T cells with distinct TCRs is not clear, ICB has been found to lead T cells infiltrating both mouse and human tumors to express components of TCR revision. Therefore, one potential mechanism by which ICB leads to anti-tumor immunity is by inducing TCR revision. Methods Wildtype C57BL/6, as well as TCR revision-deficient TCRa+/−.Rag2fl/fl.CD4cre (TCRa+/−.Rag2CD4) mice received subcutaneous injections of either 4.5 × 105 B16F10 or MC38F10 cells. Mice then received either PBS or a combination of 250 μg each of anti-CTLA-4, anti-PD-1, and anti-PDL-1 three times per week starting Day 7 after tumor cell injection. Tumor size and mouse survival were monitored, and baseline splenic and thymic immune cell numbers were measured via flow cytometry. Results No differences in T or B cell subsets were detected at baseline between the mouse strains. ICB significantly reduced tumor growth and mortality in the wildtype, but not the TCRa+/−.Rag2CD4, mice for both tumor models tested. Conclusions TCR revision capabilities seem to be important in ICB efficacy. Further investigation using these mouse models will help explore the possibility of future targeting of TCR revision pathways to increase ICB efficacy.