Abstract 2582: Silencing MICAL2 expression in pancreatic cancer cells rewires the tumor microenvironment through the IL1-a/p38 MAP kinase/STAT-3 axis and sensitizes tumors to immune checkpoint blockade therapy

Abstract Introduction: PDAC, characterized by fibroinflammatory stroma, involves cancer cell-microenvironment interactions driving progression and resistance. ChIP-seq on resected PDAC samples identified MICAL2 as a super-enhancer-associated gene involved in tumor progression. MICAL2, a flavin monooxygenase, promotes actin depolymerization and SRF transcription. This study evaluates how MICAL2 in tumor cells affects the PDAC microenvironment via the IL1-a/p38 MAP kinase/STAT3 axis. Methods: AsPC-1 and KPC-Shcontrol (ShCNT) and MICAL2 (M2KD) cells were injected to assess tumor growth. Sc-RNA seq, immunophenotyping, immunohistochemistry, and atomic force microscopy were performed on tumors. CD8+ T cells were depleted using antibodies. CD8+ T cells from M2KD tumors were adoptively transferred via tail vein injection. Anti-PD1 and anti-IL-1α antibodies were administered IP. RNA-Seq and q-PCR were performed on ShCNT and M2KD cells. PSCs were exposed to conditioned media (CM) from cancer cells with/without MICAL2, and inflammation/fibrosis gene expression was analyzed by q-PCR. Results: Orthotopic injection of KPC-M2KD cells decreased tumor growth. Sc-RNA and immunohistochemistry showed fewer CAFs in M2KD tumors. M2KD tumors had less collagen/fibronectin deposition and reduced tissue stiffness. Increased intertumoral infiltration of cytotoxic and effector CD8+T cells was observed in M2KD tumors. CD8+T cell depletion reversed M2KD tumor growth inhibition. Adoptive transfer of CD8+T cells from M2KD tumors inhibited control tumor growth. RNA-seq revealed decreased IL1-α expression in M2KD cells. IL-1R expression on PSCs was reduced cocultured with M2KD vs. control CM. PSCs co-cultured with CM from M2KD cells showed significant downregulation of IL-6, Cxcl1, and LIF. MICAL2 regulates p38 MAP kinase phosphorylation, affecting IL1-α expression and STAT3 activation, confirmed by adding a p38 inhibitor. Immune checkpoint blockade PD-1 significantly reduced M2KD tumor size; 50% of M2KD tumor-bearing mice had complete tumor regression with PD-1 and neutralizing IL-1α antibodies. Conclusion: MICAL2 mediates tumor-stromal crosstalk via the IL1-α/p38/STAT3 axis, creating an immunosuppressive PDAC environment. MICAL2 is a potential immunomodulatory target for pancreatic cancer therapy. Citation Format: Bharti Garg, Evangeline S. Mose, Edgar Esparaze, Jay Patel, Rithika Medari, Sarah Sass, Alexei Martsinkovskiy, Asmina Courelli, Gisselle Gonzalez, Adam Engler, Parag Katira, Herve Tiriac, Andrew Lowy. Silencing MICAL2 expression in pancreatic cancer cells rewires the tumor microenvironment through the IL1-a/p38 MAP kinase/STAT-3 axis and sensitizes tumors to immune checkpoint blockade therapy [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 2582.