Abstract A083: Divergent Roles of TAM Receptors in Tumor and Stromal Compartments of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options, poor prognosis, and a profoundly immunosuppressive tumor microenvironment (TME). The TAM family of receptor tyrosine kinases—Tyro3, Axl, and MerTK—are known for their roles in maintaining immune homeostasis by promoting the clearance of apoptotic cells in a non-inflammatory manner, thus preventing chronic inflammation and autoimmunity. However, their individual roles in shaping immune tolerance within the TME, especially in the context of cancer, remain unclear and may differ from their tumor-intrinsic functions, where they are often overexpressed. To dissect the host (stromal) contributions of TAM receptors in PDAC, we utilized syngeneic mouse models with targeted deletion of Tyro3 or Axl (tyro3-/- and axl-/- mice). Loss of Tyro3 in the tumor stroma, particularly in myeloid cells, significantly impaired tumor growth and was associated with enhanced type I interferon signaling and upregulation of antigen presentation pathways. In contrast, stromal deletion ofAxl modestly promoted tumor growth and failed to reverse the immunosuppressive TME, as shown by gene expression and flow cytometry analyses. When assessing metastatic potential using a splenic injection model of KPC tumor cells, liver metastases were significantly reduced in tyro3-/- mice. Conversely, stromal loss of Axl led to a marked increase in metastatic outgrowth. Since Axl is known to drive tumor cell proliferation, invasion - and is upregulated in tumor cells resistant to KRAS inhibition - we further explored its role in tumor-intrinsic versus stromal contexts. Axl knockdown in tumor cells alone had no effect on primary tumor growth but completely reversed the increased metastatic phenotype observed in Axl-deficient stroma. These findings reveal distinct and even opposing roles for Tyro3 and Axl within the host immune compartment in PDAC. While Tyro3 promotes immune evasion and tumor progression, Axl’s tumor-intrinsic expression plays a dominant role in driving metastasis. Based on these insights, we are currently testing whether co-targeting Axl and KRAS with small-molecule inhibitors could produce synergistic anti-tumor effects that outweigh potentially adverse TME consequences. Collectively, our data underscores the need to consider the unique, context-dependent roles of individual TAM receptors rather than assuming functional redundancy across the family. Citation Format: Nancy P. Kren, Alisha Holtzhausen, Doug Graham, Shelton Earp, Yuliya Pylayeva Gupta. Divergent Roles of TAM Receptors in Tumor and Stromal Compartments of 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): nr A083.