Investigating the potential of CD8α:MyD88 to restrain terminal exhaustion in tumor-specific T cells

Abstract Despite the advancements in immunotherapies for solid tumors, many patients fail to develop durable responses. The immunosuppressive and antigen persistent environment drives T cell exhaustion, interfering with the efficacy of adoptive cell therapies. Terminally exhausted T cells (TTEX) co-express inhibitory receptors, lose effector function and fail to elicit tumor control. Our lab has reported that T cells engineered to express a CD8α:MyD88 fusion protein exhibit enhanced anti-tumor activity and appear less exhausted. We hypothesize that expression of CD8α:MyD88 in T cells restrains exhaustion by transcriptionally repressing inhibitory receptor expression thereby supporting effector function, persistence, and memory. Our RNAseq and RT-qPCR data revealed that expression of inhibitory receptor genes (Havcr2, Entpd1, CD244) was lower in CD8α:MyD88 compared to CD8α T cells. Moreover, collection of CD8α:MyD88 TIL from B16-F10 tumors (10 days post transfer) exhibited reduced frequencies of TTEX (PD1+, TIM3+, CD39+) cells, greater expression of TCF1 and co-stimulatory molecules, and remained functional upon ex vivo restimulation (IFNg). Additionally, a greater frequency of central memory T cells was present in secondary lymphoid tissues. Together, our results suggest that expression of CD8α:MyD88 in T cells may interfere with the expression of inhibitory receptors that dampen the anti-tumor response, thus enhancing the functional longevity and memory potential of T cells.