Abstract 6912: Resolvin E1 sensitizes tumors to immune checkpoint inhibition by stimulating tumor antigen presentation

Abstract Background: Immune-checkpoint inhibitors (ICI) unleash tumor-specific cytotoxic T cells already primed to recognize tumor-associated antigens (TAA). One reason for poor response to ICI is insufficient priming of T cells, which requires cross-presentation of TAA to T cells by innate immune cells. Phagocytosis of apoptotic tumor cell by antigen-presenting innate immune cells is crucial for priming T cells to TAA, but without proper adjuvant signals, it can lead to immunosuppression. The endogenous lipid mediator Resolvin E1 (RvE1), a partial agonist of the BLT1 receptor, promotes phagocytosis of tumor cell debris and has been shown to control solid tumor growth in animal models. However, its effect on antigen presentation remains unknown. Methods: We studied the efficacy of TP-317, a clinical stage RvE1 drug, in murine tumor models implanted subcutaneously (Lewis Lung carcinoma (LLC), CT26 colon carcinoma, B16F10 melanoma, KPC pancreas adenocarcinoma). After tumor volumes reached ≥ 100mm3, animals were treated with TP-317 (0.3 mg/kg, po, qd; or 300 ug/kg, s.c., q6d) alone or in combination with ICI or chemotherapy or both (n=8-9/group). Tumors were resected at days 9-12 and analyzed by bulk and/or single cell RNAseq. Results: TP-317 monotherapy suppressed primary tumor growth on average by 31% in LLC, 66% in B16F10, 46% in CT26 and by 36% in KPC, rivaling the canonical ICI + chemo in these models. While TP-317 exhibited additivity when combined with chemotherapy (cisplatin, 5-FU and gemcitabine + paclitaxel in LLC, CT26 and KPC, respectively) or ICI (anti-PD1 +/- anti-CTLA4), TP317 synergistically enhanced tumor control in combination with ICI + chemo or with dual ICI, reducing tumor growth by an additional 60-80% compared to the various dual combinations alone. The effect of TP-317 monotherapy required the presence of CD8 T cells and was largely abrogated in animals co-treated with a BLT1 antagonist. Whole-tumor transcriptomes of resected tumors of TP-317-treated versus control animals displayed a broad upregulation of IFN-γ response genes, including antigen presentation machinery, regulators of MHC loci, immunoproteasome and MHC-I/II, as well as genes activating T-cell, NK cell and dendritic cell interaction. Single-cell RNAseq of B16F10 and LLC located the source of such transcriptional activation to innate immune cells. Intriguingly, antigen presentation genes (including MHC-II) were also markedly induced in tumor cells. Conclusion: These data demonstrate the potent antitumor activity of TP-317, notably when combined with ICI and chemotherapy. This synergism may be explained by the dual effect of cross-presentation of TAA to prime T cells and presentation of TAA on tumor cells, sensitizing them to cytotoxic T cells. Thus, TP-317 holds promise as novel adjunct treatment for cancers that are currently treated with immunotherapy targeting T cell exhaustion but show limited response. Citation Format: Sui Huang, Katherine Quinlinvan, Eva Rothenberg, Michael Gillespie, Nandini Krishnamoorthy, Wayne D. Klohs, John Parkinson, Gary Mathias, Dipak Panigrahy. Resolvin E1 sensitizes tumors to immune checkpoint inhibition by stimulating tumor antigen presentation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6912.