Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers

Significance Immune checkpoint blockade (ICB) to reinvigorate cytotoxic T lymphocytes using antibodies against CTLA4 or PD1 generates durable therapeutic responses in patients across a variety of cancer types. However, some cancers such as castration-resistant prostate cancer (CRPC) show overwhelming resistance to ICB. Here, we develop a nitroproteomic approach and uncover a potential mechanism for the immunotherapy resistance where a key protein for T cell activation, lymphocyte-specific protein tyrosine kinase (LCK), is nitrated and inactivated by myeloid-derived suppressor cell–generated reactive nitrogen species (RNS) in the resistant tumor. An agent that neutralizes RNS significantly sensitizes CRPC to ICB therapy in a mouse model. Therefore, our studies illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of ICB-resistant cancers.