Abstract B006: Actin Cytoskeleton Dynamics in Tumor Cells Orchestrate Stromal Desmoplasia and Immune Evasion in Pancreatic Cancer
Bharti Garg, Evangeline Sari. Mose, Briana Nyugen, Ponmathi Panneerpandian, Phillip Salu, Edgar Esparza, Jay Patel, Kevin Gulay, Rithika Medari, Sarah Sass, Jonathan Weitz, Alexei Martsinkovskiy, Asmina Courelli, Jaiyu Chen, Minya Pu, Karen Messer, Carrie Bishop, Gisselle Gonzalez, Adam Engler, Parag Katira, Vivien Ileana . Maltez, Herve Tiriac, Andrew M. LowyAbstract
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is defined by a dense, immunosuppressive tumor microenvironment (TME) enriched with extracellular matrix components, cancer-associated fibroblasts (CAFs), and diverse immune populations. ChIP-seq analysis of resected human PDAC identified MICAL2 as a super-enhancer–associated gene. MICAL2, a flavin monooxygenase that regulates actin depolymerization and SRF-dependent transcription, emerged as a candidate driver of PDAC stromal and immune remodeling. This study investigates how tumor-intrinsic MICAL2 shapes the PDAC TME.
Methods:
Orthotopic implantation of inducible KPC ShCTRL and ShMICAL2 knockdown cells was used to assess tumor growth. Immunofluorescence, flow cytometry, and atomic force microscopy evaluated stromal composition and stiffness. Single-cell RNA sequencing and CellChat analyses characterized immune and stromal interactions. CD8+ T-cell depletion and adoptive T-cell transfer tested immune dependence. RNAScope assessed cytokine expression and signaling. KPCM tumors and cell lines expressing wild-type or mutant MICAL2 (ΔNLS or FAD-deficient) evaluated transcriptional requirements. Anti–PD-1 and IL-1α blockade tested therapeutic response. Organotypic Human PDAC slice cultures were treated with MICAL2 antisense oligonucleotides (ASOs) to evaluate the changes in the Immune microenvironment.
Results:
ShMICAL2 tumors showed reduced growth and increased cellularity, with marked loss of PDPN+ and α-SMA+CAFs, diminished collagen and fibronectin deposition, and decreased stiffness. MICAL2 loss reprogrammed CAF gene expression and enhanced infiltration of activated CD8+ T cells, with macrophage polarization shifting from M2 to M1 phenotype. Single-cell RNA sequencing revealed increased cycling T cells and plasma cells, while CellChat demonstrated strengthened T-cell communication and reduced tumor–CAF signaling in ShMICAL2 tumors. CD8+T cell depletion reversed tumor suppression in both immune-hot and immune-cold models, and adoptive transfer of ShMICAL2 tumor-infiltrating lymphocytes suppressed control tumors. KPC46 ShMICAL2 cells and tumors displayed reduced IL-1α, IL-6, and TGF-β expression and decreased p38/STAT3 phosphorylation. Aspc-1 ShMICAL2 cells showed reduced NF-κB reporter activity, and inhibiting p38/IL-1A in ShControl and ShMICAL2 cells further reduced it. MICAL2 mutants (ΔNLS or FAD-deficient) impaired tumor growth, reduced stromal expansion, diminished SRF activity, and increased CD8+ T-cell infiltration. Anti–PD-1 therapy further reduced ShMICAL2 tumor size, and combined anti–PD-1/IL-1α blockade induced complete regression in 50% of mice. In human PDAC slice cultures, MICAL2 antisense oligonucleotides increased T-cell activation and M1 macrophage polarization.
Conclusion:
MICAL2 functions as a central regulator of PDAC immunosuppression, promoting stromal expansion, CAF activation, and inhibitory cytokine signaling. Loss of MICAL2 remodels the TME toward enhanced immune activation and therapeutic responsiveness, positioning MICAL2 as a promising target for PDAC treatment.
Citation Format:
Bharti Garg, Evangeline Sari. Mose, Briana Nyugen, Ponmathi Panneerpandian, Phillip Salu, Edgar Esparza, Jay Patel, Kevin Gulay, Rithika Medari, Sarah Sass, Jonathan Weitz, Alexei Martsinkovskiy, Asmina Courelli, Jaiyu Chen, Minya Pu, Karen Messer, Carrie Bishop, Gisselle Gonzalez, Adam Engler, Parag Katira, Vivien Ileana . Maltez, Herve Tiriac, Andrew M. Lowy. Actin Cytoskeleton Dynamics in Tumor Cells Orchestrate Stromal Desmoplasia and Immune Evasion in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B006.