| First Author | Hänggi K | Year | 2024 |
| Journal | Cancer Cell | Volume | 42 |
| Issue | 12 | Pages | 2015-2031.e11 |
| PubMed ID | 39577420 | Mgi Jnum | J:360628 |
| Mgi Id | MGI:7787975 | Doi | 10.1016/j.ccell.2024.10.014 |
| Citation | Hanggi K, et al. (2024) Interleukin-1alpha release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity. Cancer Cell 42(12):2015-2031.e11 |
| abstractText | 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 generates a myeloid suppressive microenvironment that inhibits T cell function, promotes tumor growth, and reduces survival. This was dependent upon the release of the nuclear alarmin interleukin-1alpha (IL-1alpha) by dying cells. Critically, IL-1alpha release occurs during chemotherapy and targeting this molecule reduces the immunosuppressive capacity of tumor myeloid cells and promotes CD8(+) T cell recruitment and effector function. Neutralizing IL-1alpha enhances the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. Low IL1A levels correlates with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy. |
