Antibody Mediated Crosslinking Of Cd38 Triggers Costimulatory Signaling And Promotes T Cell Effector Function.

Abstract CD38 is a multi-functional ecto-enzyme that regulates NAD+ metabolism. Monoclonal antibodies against CD38, including daratumumab and isatuximab have been successfully developed to treat patients with multiple myeloma, a cancer known to express high levels of CD38. However, CD38 is also expressed by normal immune cells, including B, NK, myeloid and T cell subsets. Using monoclonal antibodies against CD38, we show that CD38 crosslinking can augment T cell antigen receptor signaling, leading to enhanced T cell proliferation and cytokine production. Gene profiling analysis supports the contention that anti-CD38 ligation promotes T cell activation. Studies of CD38 mutants demonstrate that the co-stimulatory effect of anti-CD38 is independent of the ecto-enzymatic activity of CD38. Further analysis of activated CD4 T cells by mass spectrometry shows that CD38 is in close proximity with multiple adhesion and co-stimulatory molecules, including LFA-1, ICOS and OX40. These data support a role for CD38 as a co-stimulatory molecule in T cells, independent of its enzymatic activity. Citation Format: Mun Kyung Hwang, Anlai Wang, Zhili Song, Shujia Dai, Bailin Zhang, Joachim Theilhaber, Lily Pao, Dmitri Wiederschain, Chen Zhu. Antibody mediated crosslinking of CD38 triggers costimulatory signaling and promotes T cell effector function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1632.