Modulation of CD8+ T cell antitumor function by an immune inhibitory molecule sushi domain containing 2

Abstract A central mechanism by which the immunosuppressive tumor microenvironment (TME) facilitates tumor growth is the inhibition of CD8+ effector T cell function. Indeed, restoration of CD8+ T cell antitumor functions by immune checkpoint blockade (ICB) treatment represents a significant breakthrough in cancer therapy. However, a major challenge remaining in ICB immunotherapy is the existence of multiple immune checkpoint molecules. As a result, targeting of a single molecule cannot override compensatory signals from other immune inhibitory molecules. Therefore, there is an urgent need to identify new therapeutic target(s) to rejuvenate CD8+ T cell antitumor immunity for cancer therapy. Through unbiased gene profiling assay, our recent study has identified SUSD2 (sushi domain containing 2) as a highly expressed immune cell-associated cell surface molecule in an experimental cancer model. Using a newly developed Susd2 gene-deletion (Susd2−/−) mouse model, we found that genetic deletion of Susd2 led to an improved control of tumor growth in syngeneic tumor models including colorectal carcinoma MC38 and thymoma EG7. This improved tumor control phenotype of Susd2−/− mice required the presence of CD8+ T cells. Single-cell RNA sequencing assay revealed increased production of effector molecules such as granzyme B (Gzmb) and interferon (IFN)-γ in tumor-infiltrating CD8+ T cells from Susd2−/− mice compared to those from wild-type (WT) mice. Mechanistically, we found that SUSD2 negatively regulated IL-2 receptor (IL-2R)-mediated generation of Gzmb and IFN-g in CD8+ T cells. In sum, our results identify SUSD2 as a new immune inhibitory molecule which can be targeted to augment CD8+ T cell antitumor response.