Interleukin-1a 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. Overall design: PyMT C57 mouse tumor cells expressing non-targeting control (NTC) or Il1a-targeting guide RNA together with Cas9 were implanted into mammary fat pad of female C57BL/6 mice at 8 weeks of age. Tumors were harvested 14 days post implantation in the absence of any treatment and tumor volume did not show any difference between groups. CD45 positive cells were harvested from these tumors by fluorescence-activated cell sorting on a FACS ARIA II and used for single cell sequencing analysis.