Abstract A094: Myofibroblast programming blocks differentiation of immune enhancing fibroblastic reticular cells in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is considered an immunologically cold cancer type. This perception is due to its rapid progression, strong presence of immunosuppressive cells and lack of response to current immunotherapies. However, we and others have shown that many patient PDAC tumors contain robust lymphocyte infiltration, aggregated in the form of tertiary lymphoid structures (TLS). The presence of TLS in PDAC is prognostic for long-term survival and in other cancer types, predictive of response to immunotherapy. Despite the clinical benefit to generating TLS in tumors, why they form in some PDAC patients but not others, remains unknown. The desmoplastic stroma in PDAC contributes to defective anti-tumor immunity largely due to myofibroblastic cancer associated fibroblasts (myCAF) induced by transforming growth factor-beta (TGFb). Other groups have demonstrated that mesenchymal cell phenotypes with lymphoid tissue organizing properties regulate TLS formation in other tumor types. In order to restore effective anti-tumor immunity for PDAC patients, CAF phenotypes must be reprogrammed to support rather than restrict intratumoral immune activity. Using a lymphotoxin beta receptor (LTBR) agonist we observed the induction of TLS-like aggregates in some murine PDAC tumor models, but not others. The CAF phenotypes of TLS-resistant models were predominantly myCAF while the TLS-permissive models were enriched for a VCAM1+ICAM1+ reticular-CAF (rCAF) subset. Induction of myCAF differentiation in vitro with TGFb1 silenced LTBR/TNFR mediated upregulation of CXCL13 and CCL19 chemokine expression and diminished B and T cell migration towards fibroblasts. Therapeutic TGFbR1 inhibition in tumor bearing mice abrogated these effects thereby allowing LTBR agonism to repolarize rCAF phenotypic programming associated with improved lymphocyte recruitment and T cell-dependent tumor control. In patient PDAC tumors, rCAF were spatially arranged encapsulating TLS while myCAF were located distally. These data indicate that myCAF-regulated PDAC stroma antagonizes acquisition of rCAF subsets critical for TLS formation but can be therapeutically remodeled to promote beneficial immune responses in PDAC tumors. Citation Format: Andrew J. Gunderson, Elijah Kirschstein, Olivia Harder, Jordan Krull, Madison Sikorski, Shrijan Khanal, Morgan Mack, Carl F. Ware, Elizabeth Evans, Michael J. Gough, Qin Ma, Wei Chen, Kristina Young. Myofibroblast programming blocks differentiation of immune enhancing fibroblastic reticular cells in pancreatic cancer [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(18_Suppl_3):Abstract nr A094.