Graduate student The Ohio State University College of Medicine Columbus, Ohio, United States
Introduction/Rationale: T cell exhaustion, characterized by gradual reduction of T cell effector function in the tumor microenvironment, is a key mechanism behind poor patient response to cancer immunotherapy. Our recent study has identified the Sushi domain containing 2 (SUSD2), a cell surface protein in CD8+ T cells, as an inhibitory factor that limits the survival and effector function of intratumoral CD8+ T cells through suppression of IL-2 signaling. However, the mechanistic contribution of SUSD2 towards T cell exhaustion remains largely unknown.
Methods: To better understand how persistent antigen stimulation might contribute to the differential development of T cell exhaustion in Susd2-deficient (Susd2-/-) CD8+ T cells, we utilized an in vitro model that has been shown to recapitulate the in vivo hallmarks of T cell exhaustion. We also performed spatial transcriptomics analysis on malignant melanoma patient sample via 10X Genomics Visium Spatial Platform to map SUSD2 expression to CD8+ T-cell exhaustion gene signatures in situ across tumor regions.
Results: We detected an increased population of TCF-1+ precursor T cells (Tpex), but decreased terminally exhausted PD-1+Tim-3+ T cells (Ttex), in Susd2-/- CD8+ T cells upon chronic antigen stimulation, which is associated with improved cancer prognosis. Spatial transcriptomics of malignant melanoma tumor showed that SUSD2 overexpression was associated with highly exhausted T-cell gene signature within the tumor microenvironment.
Conclusion: Collectively, these results suggest the detrimental function of SUSD2 driving the transition of CD8+ T-cells from Tpex to Text phenotype in the tumor microenvironment in response to chronic antigen stimulation, with potential applications to novel immunotherapies such as IBC or adoptive T-cell therapy.
