Defects in the necroptosis machinery are a cancer resistance mechanism to checkpoint inhibitor immunotherapy

• DOI: 10.1136/jitc-2024-010433
• Publication Date: 2025-05-09T05:55:18Z
• Authors: Anna Sax; Peter May; Stefan Enssle; Nardine Soliman; Tatiana Nedelko; Giada Mandracci; Fabian Stögbauer; Laura Joachim; Christof Winter; Florian Bassermann; Katja Steiger; Nadia El Khawanky; Hendrik Poeck; Simon Heidegger
• Keywords: Cancer Immunotherapy; Immune checkpoint

Background Immune checkpoint inhibitors (ICIs) of programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell immune responses against tumor cells. For many patients, these therapies fail because the development spontaneous is often compromised, as microenvironment (TME) lacks proinflammatory signals resulting in suboptimal activation antigen-presenting cells (APCs). Necroptosis a special form associated with leakage inflammatory factors that can lead to APC maturation. However, it unclear which extent functional necroptosis contributes ICI immunotherapy. Methods With genetically engineered lines lack specific components machinery (mixed lineage kinase domain-like pseudokinase (MLKL), receptor interacting 3 (RIPK3)), we addressed importance necroptotic for efficacy immunotherapy murine models. Preclinical data were aligned genome-wide transcriptional programs patient samples at diagnosis and during treatment activity pathways association outcome. Results Mice bearing MLKL-deficient RIPK3-deficient tumors failed control growth response anti-PD-1/anti-CTLA-4 Mechanistically, defects pathway resulted reduced antigen cross-presentation by type 1 conventional dendritic (DCs) tumor-draining lymph nodes, subsequently impaired immunotherapy-induced expansion circulating antigen-specific CD8 + T their accumulation TME. In vitro, co-culture undergoing but not apoptotic increased uptake phagocytic cells, maturation DCs. Treatment epigenetic modulator azacytidine enhanced intrinsic machinery, hence susceptibility humans, transcriptome analysis melanoma revealed between high expression MLKL prolonged overall survival durable clinical anti-PD-1 and/or anti-CTLA-4 inhibitors. Conclusions Defective signaling cancer resistance mechanism Reversion silencing render susceptible inhibition.