Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity

Necroptosis can promote antigen-specific immune responses, suggesting induced necroptosis as a therapeutic approach for cancer. Here we sought to determine the mechanism of immune activation but found the necroptosis mediators RIPK3 and MLKL dispensable for tumor growth in genetic and implantable models of breast or lung cancer. Surprisingly, inducing necroptosis within established breast tumors generated a myeloid suppressive microenvironment that inhibited T cell function, promoted tumor growth, and reduced survival. This was dependent upon the release of the nuclear alarmin interleukin 1a(IL1a) by dying cells. Critically, IL1arelease occurred during chemotherapy and targeting this molecule reduced the immunosuppressive capacity of tumor myeloid cells and promoted CD8+ T cell recruitment and effector function. Neutralizing IL1a enhanced the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. LowIL1Alevels correlated with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.