Abstract A020: Coronin 1C Orchestrates Stromal Remodeling and Immune Exclusion to Drive Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma
Sashikanta Swain, Kartik Muduli, Pravash Ranjan. Mishra, Sarojini Raman, Bramhadatta Pattnaik, sibanarayana padhiAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplastic stromal remodeling, profound immune exclusion, and resistance to chemotherapy and immunotherapy. Although Coronin 1C (CORO1C) has been implicated in tumor progression, its role in orchestrating stromal remodeling and CD8+ T-cell exclusion remains poorly understood. Here, we investigated the biological and translational significance of CORO1C using integrated transcriptomic, spatial, molecular, imaging, and functional approaches.
Methods:
A multi-platform translational strategy was employed integrating TCGA transcriptomic analysis, single-cell RNA sequencing, spatial transcriptomics, serial IHC analysis of 108 surgically resected PDAC specimens, Western blotting, ELISA, 68Ga-FAPI PET/CT imaging, patient-derived organoids, ex vivo tumor slice cultures, Transwell T-cell migration assays, T-cell receptor signaling analysis, and orthotopic mouse models. Functional validation was performed using esiRNA and lentiviral-mediated CORO1C knockdown.
Results:
Transcriptomic analyses demonstrated that CORO1C was significantly overexpressed in malignant epithelial cells and was associated with extracellular matrix remodeling, immune checkpoint signaling, T-cell exhaustion, chemokine signaling, and immunotherapy resistance. Spatial transcriptomic analysis further revealed that CORO1C high tumor regions spatially colocalized with activated fibroblast populations and markedly reduced CD8+ T-cell infiltration, confirming the spatial organization of immune exclusion within the PDAC tumor microenvironment. Histopathological validation demonstrated progressive increases in CORO1C expression, α-SMA expression, collagen deposition, and stromal activation with advancing tumor grade, accompanied by exclusion of CD8+ T cells from the tumor center. Higher circulating CORO1C levels in patients demonstrated their utility as a biomarker. Patient-derived organoids established from CORO1C-high tumors exhibited significantly reduced CD8+ T-cell infiltration, whereas CORO1C silencing in ex vivo tumor slice cultures restored T-cell penetration into tumor tissue. Similarly, CORO1C knockdown significantly enhanced T-cell migration, restored proximal T-cell receptor signaling, and promoted intratumoral CD8+ T-cell accumulation in orthotopic PDAC mouse models. Collectively, these findings establish CORO1C as a central regulator linking stromal remodeling with immune exclusion in PDAC.
Conclusions:
CORO1C coordinates a multidimensional program of PDAC progression by activating TGF-β-dependent stromal remodeling, promoting extracellular matrix deposition, and establishing an immune-excluded tumor microenvironment through impaired CD8+ T-cell infiltration and dysfunction. Restoration of antitumor T-cell infiltration following CORO1C inhibition across patient-derived organoids, ex vivo tumor slices, and orthotopic mouse models highlights CORO1C as a therapeutic target for overcoming stromal- and immune-mediated therapeutic resistance in PDAC.
Citation Format:
Sashikanta Swain, Kartik Muduli, Pravash Ranjan. Mishra, Sarojini Raman, Bramhadatta Pattnaik, sibanarayana padhi. Coronin 1C Orchestrates Stromal Remodeling and Immune Exclusion to Drive Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma [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 A020.