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Abstract Checkpoint blockade therapies have transformed the landscape of cancer care. Durable clinical responses have been observed in a subset of patients. However, many patients do not respond, and understanding the mechanisms that determine tumor resistant to checkpoint blockade drugs could potentially benefit more patients. Ferroptosis is a relatively newly described form of regulated cell death distinct from apoptosis and necroptosis. Recently, T cell-promoted tumor ferroptosis was shown to be an anti-tumor mechanism and targeting this pathway could be a potential therapeutic approach. To identify genes critical to immunotherapy resistance, B16. SIY cells were transduced with a genome-scale gRNA lentivirus to generate loss of function mutants. In vitro-primed CD8+ T cells isolated from 2C/Rag2-/- TCR transgenic mice specific for the SIY antigen were co-cultured with transduced B16. SIY tumor cells. Resistant mutants were identified by deep sequencing of survival clones. The gene encoding Decr2, a peroxisomal 2, 4-dienoyl-CoA reductase, was identified. Decr2 mutants were relatively resistant to CD8+ T cell killing in vitro. Consistent with this resistance to CD8+ T cell killing, Decr2 knock-down tumors showed minimal response to anti-PD-L1 therapy in vivo. Tumor microenvironment analysis in Decr2 knockdown B16. SIY tumors showed failed antigen specific CD8+ T cells’ expansion and less IFN-γ production after anti-PD-L1 treatment. Knock-down of Decr2 resulted in diminished ferroptosis, triggered either by pharmacologic inducers or antigen-specific CD8+ T cells. Mechanistic studies revealed that Decr2 knockdown resulted in diminished induction of polyunsaturated ether phospholipids (PUFA-ePLs), which is due to reduced polyunsaturated ether phospholipids synthesis rate. Analysis of melanoma tumors from human patients revealed that up-regulation of Decr2 was associated with anti-PD-1 efficacy. Our results proved Decr2 knock down suppressed tumor ferroptosis and confer tumors resistance to anti-PD-L1 therapy by reducing the polyunsaturated ether phospholipids (PUFA-ePLs) synthesis. Citation Format: Shuyin Li, Jason Shapiro, Hardik Shah, Emily F. Higgs, Lishi Xie, Yuanyuan Zha, Jonathan Trujillo, Alexandra Cabanov, Tyler A. Jones, Blake Flood, Ken Hatogai, Justin Kline, Thomas F. Gajewski. Decr2 regulates tumor cell ferroptosis and immunotherapy efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5350.
Li et al. (Fri,) studied this question.