HVEM blockade initiates tumor cell death by innate immunity and improves anti-tumor response by human T cells in NSG immuno-compromised mice

Members of the TNF receptor superfamily (TNFRSF) are attractive targets for cancer immunotherapy. Here, we investigated the impact on tumor growth of a murine monoclonal antibody to human TNFRSF14 (HVEM) in PBMC-humanized NSG mice. We first showed that injection of the anti-HVEM monoclonal antibody led to a reduction in the growth of a human HVEM-expressing prostate cancer cell line, associated to an increase in the proliferation and number of TIL. These results were not reproduced if the tumor was engineered not to express HVEM by CRISPR/Cas9. We observed a similar effect of the antibody on tumor growth in non-humanized NSG mice that was also lost with the HVEM-deficient cell line. These results suggest that the antibody exerted its anti-tumor effect by directly binding to tumor cells. However, in vitro microscopy analysis showed that the antibody alone had no significant effect on tumor survival. In contrast, addition of peritoneal macrophages from NSG mice to the culture resulted in tumor killing and slower growth of the tumor, suggesting that innate immunity of NSG mice participated in tumor control in vivo. Finally, we reproduced the in vivo anti-tumor effect of the antibody on a human melanoma HVEM+ cell line, suggesting that the therapy could be applied to various HVEM+ cancers. Altogether, our results suggest that therapeutic efficacy of the antibody is associated to cell death mediated by innate immune cells, allowing subsequent human T cell-mediated immunity to control tumor growth.