IL-1R1 on distinct immune cells can strongly enhance or inhibit tumor immunity

Inflammation is necessary for defense against pathogens, but chronic inflammation can promote tumor growth and enable tumors to escape from immune-mediated destruction. Recently, we demonstrated that deficiency of IL1β favors antitumor immunity, and multiple clinical trials involving antibody mediated IL1β blockade in multiple cancers are underway. We showed that IL1α signaling was required for IL1β blockade-induced antitumor immunity, leading to the hypothesis that its interaction with the IL1 type I receptor (IL1R1) was required for the antitumor immune response. To determine which cell type required the IL1α signal, we studied the antitumor immune response in several mouse lines where the IL1R1 was conditionally deleted in T cells (LckCre), dendritic cells (CD11cCre), or macrophages (LysMCre) and on an IL1β -sufficient or -deficient background. When IL1R1 was absent in the T cell compartment the augmented control of MC38.OVA tumor growth in IL1β -deficient mice was lost. This indicated that IL1α signaling through T cells enabled the anti-tumor response. Deletion of IL-1R in DC had no effect. To determine the contribution of other cells, we measured the growth of MC38.OVA tumors in mice where the IL1R was absent on monocytes/macrophages. Strikingly, conditional deletion of IL1R in monocytes/ macrophages further delayed tumor growth beyond the substantial tumor inhibition in IL1β-deficient mice. This also corresponded to an increase in XCR1+ cDC1 cells. Given that the in vivo injection of tumor cells is an inflammatory process, we expanded our study to the autochthonous BRafCA/+/PTENloxp/ R26EGFPOVA/Tyr;;CreERT2 (BPO) mouse model on an IL1β–/– background. In BPO/IL1β–/– tumors fewer CD8 TILs expressed PD-1 (20.1±1.9 vs. 9.3±1.0 S.E.M.), which correlated with fewer EGFP-OVA+tumor cells. We propose that IL1α costimulation of T cells promotes antitumor immunity, but this is strongly antagonized by activation of monocytes/macrophages by IL1β, leading to tumor immune suppression by MDSC and tumor macrophages. Manipulating this balance may help optimize IL-1b blocking therapy in tumor immunity.