Abstract PDAC is defined by a dense, immunosuppressive TME composed of ECM proteins, CAFs, and diverse immune cells. ChIP-seq on resected human PDAC samples identified MICAL2 as a super-enhancer-associated gene and its high expression was corelated with poor survival of patients. MICAL2, a flavin monooxygenase, promotes actin depolymerization and SRF transcription. This study investigates how tumor-intrinsic MICAL2 alters the PDAC TME. Orthotopic implantation of KPC-MICAL2 knockdown (M2KD) inducible cells led to reduced tumor growth. Immunofluorescence, flow cytometry, and atomic force microscopy showed M2KD tumors were more cellular, with marked reduction in PDPN+/α-SMA+ CAFs, collagen, and fibronectin, resulting in reduced stiffness. MICAL2 loss also reprogrammed CAF gene expression and increased infiltration of activated CD8+ T cells, skewing from an M2 to M1 macrophage phenotype. scRNA-seq revealed major shifts in immune populations, including increased cycling T and plasma cells. CD8+ T cell depletion reversed tumor suppression in both immune-hot and immune-cold syngeneic models, and adoptive transfer of MICAL2-KD tumor-infiltrating T cells suppressed the growth of control tumors. RNAScope showed reduced IL-1α, IL-6, TGF-β expression and decreased p38 and STAT3 phosphorylation in MICAL2-KD tumors. To test if MICAL2 regulates PDAC TME transcriptionally, we generated KPCM tumors and lines (by crossing PDX1-Cre; LSL-KRAS G12D/+; P53R172H/WT (KPC) with Mf/f mice) and reintroduced WT MICAL2 and MICAL2 lacking nuclear localization signal (DNLS) or FAD enzymatic domain in KPCM line. DNLS and FAD point mutant MICAL2 cells were deficient in tumor growth, had reduced stromal deposition and SRF activity, and increased CD8+ T cells. Anti-PD-1 significantly reduced M2KD tumor size and 50% of M2KD tumor-bearing mice had complete regression with anti-PD-1 and IL-1α antibodies. MICAL2-ASO treatment in human PDAC ex-vivo slice cultures increased T cell activation and M1 polarization. MICAL2 drives immunosuppression in PDAC and could be a potential therapeutic target. Citation Format: Bharti Garg, Evangeline Sari. Mose, Edgar Esparza, Jay Patel, Kevin Gulay Gulay, Sarah Sass, Alexei Martsinkovskiy, Asmina Courelli, Carrie Bishop, Gisselle Gonzalez, Adam Engler, Parag Katira, Vivien Ileana. Maltez, Herve Tiriac, Andrew M. Lowy. Actin cytoskeleton dynamics in tumor cells mediate Immune-suppressive microenvironment and sensitize pancreas tumors to PD-1 blockade therapy abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A109.
Garg et al. (Sun,) studied this question.
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