c-Rel is a myeloid checkpoint for cancer immunotherapy

Abstract

Immunotherapy that targets lymphoid cell checkpoints holds great promise for curing cancer. However, many cancer patients do not respond to this form of therapy. In addition to lymphoid cells, myeloid cells play essential roles in controlling immunity to cancer. Whether myeloid checkpoints exist that can be targeted to treat cancer is not well established. Here we show that c-Rel, a member of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) family, specified the generation of myeloid-derived suppressor cells by selectively turning on protumoral genes while switching off antitumoral genes through a c-Rel enhanceosome. c-Rel deficiency in myeloid cells markedly inhibited cancer growth in mice and pharmaceutical inhibition of c-Rel had the same effect. Combination therapy that blocked both c-Rel and the lymphoid checkpoint protein programmed cell death protein 1 was more effective in treating cancer than blocking either alone. Thus, c-Rel is a myeloid checkpoint that can be targeted for treating cancer.