The Role of CD38 in Anti-tumor Immunity and Tumor Immune Evasion

Abstract

CD38 is a multifunctional protein that is expressed in many immune cells, modulating NAD metabolism, inflammation and oxidative stress. Recent studies suggest that CD38 is also implicated in tumor immunosuppression. However, the role of CD38 in anti-tumor immunity and tumor immune evasion, and mechanisms involved, are still unclear. We hypothesized that CD38 expression by immune cells constricts T cell-mediated anti-tumor immune responses and promotes tumor cell immune evasion. We investigated whether mice lacking CD38 (CD38^–/–) had impaired tumor growth in subcutaneous, intraperitoneal and intravenous syngeneic tumor models. CD38^–/– mice showed no difference in subcutaneous B16 melanoma tumor growth and pulmonary B16 tumor metastases, compared to wild-type (WT) C57BL/6 (B6) mice. Conversely, CD38^–/– mice had decreased tumor burden in intraperitoneally-inoculated EG7 thymoma and ID8 ovarian tumor models. Since the omentum is a major site of metastasis for intraperitoneal tumors, we immunophenotyped the omentum. In naïve mice and tumor models, we observed significantly less regulatory T cells (Tregs), and increased CD8/Treg ratio in the omentum of CD38^–/– mice. No difference in Treg number was observed, suggesting that this phenotype is specific to the omentum. Given the well-established contribution of CD38 enzymatic activity in effective immune responses, we hypothesized that CD38 enhances the immunosuppressive potential of Tregs. We noted decreased GITR+ and PD+ Tregs in omentum, but no difference in naïve mice and ID8 model. To determine whether theenzymatic production of calcium-mobilizing molecules by CD38 was important for omental Treg survival, proliferation and/or tissue localization, we enumerated Tregs in the omentum of mice lacking TRPM2 (TRPM2^–/–), a calcium channel activated by ADP-ribose. ADP-ribose is a major product of CD38 NAD-catabolizing activity. TRPM2^–/– mice had no difference in the number of omental Tregs compared to their WT counterparts. Next, we administered nicotinamide (NAM) to naïve CD38^–/– mice to determine whether omental Treg depletion in these mice could be reversed by supplementation with NAM addition. We saw omentum-specific Tregs recovery in CD38^–/– mice, but whether this recovery is CD38-specific remains to be determined.