2. Academic Validation
  3. Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity

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

  • Cancer Cell. 2024 Nov 13:S1535-6108(24)00402-1. doi: 10.1016/j.ccell.2024.10.014.
Kay Hänggi 1,  Jie Li 2,  Achintyan Gangadharan 2,  Xiaoxian Liu 3,  Daiana P Celias 4,  Olabisi Osunmakinde 2,  Aysenur Keske 4,  Joshua Davis 3,  Faiz Ahmad 5,  Auriane Giron 4,  Carmen M Anadon 4,  Alycia Gardner 2,  David G DeNardo 5,  Timothy I Shaw 3,  Amer A Beg 4,  Xiaoqing Yu 3,  Brian Ruffell 6
Affiliations

Affiliations

  • 1 Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: kay.hanggi@moffitt.org.
  • 2 Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA.
  • 3 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 4 Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 5 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 6 Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: brian.ruffell@moffitt.org.
PMID: 39577420 DOI: 10.1016/j.ccell.2024.10.014
Abstract

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-1α (IL-1α) by dying cells. Critically, IL-1α 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-1α 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.

Keywords

cancer; chemotherapy; immunogenic cell death; immunosuppression; interleukin-1; macrophages; necroptosis; necrotic-like cell death; neutrophils.

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