A Role for TLR2 in Regulating Immune Surveillance in Pancreatic Ductal Adenocarcinoma

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ABSTRACT Immunotherapy has shown remarkable benefit for some patients with solid cancers. However, it has largely been ineffective for the treatment of pancreatic ductal adenocarcinoma (PDAC). Notably, cancers with liver metastasis often show decreased responsiveness to immunotherapy and PDAC commonly metastasizes to the liver. Our lab has previously shown that PDAC triggers liver inflammation during early disease pathogenesis that subsequently supports metastasis to the liver. However, it remains unclear how the liver might influence outcomes to immunotherapy. The liver is classically known as an immunoregulatory organ involved in regulating T cell tolerance. Preliminary data show that serum amyloid A (SAA) proteins released by the liver in the setting of PDAC development suppress T cell surveillance in mouse models of PDAC such that genetic deletion of SAA converts PDAC tumors from T cell “poor” to T cell “rich”. SAA are known to signal through toll-like receptor 2 (TLR2) and consistent with this, preliminary data also show that genetic deletion of TLR2 causes T cell infiltration into PDAC tumors even in the presence of high levels of SAA. This finding implicates the SAA/TLR2 signaling pathway as a determinant of T cell surveillance in PDAC. However, little is known about how TLR2 regulates T cells surveillance in cancer. It is the central hypothesis of this proposal that TLR2 signaling causes sequestration of tumor-specific effector T cells in the liver which then undergo apoptosis, thereby limiting productive T cell surveillance in PDAC. To test this hypothesis, in Aim One I will define cellular mechanisms by which TLR2 regulates T cell surveillance in PDAC. In Aim Two, I will determine the impact of TLR2 on tumor-specific T cell fate and the efficacy of T cell immunotherapy. Altogether, studies in this proposal will improve our understanding of the role of tumor-extrinsic features in regulating immune resistance in PDAC with the aim to identify novel strategies for improving the efficacy of immunotherapy. This project will be sponsored by an established mentor with expertise in cancer immunology and tumor biology. This sponsorship entails a strong commitment to mentorship at an institution with an exceptional environment for training in cancer immunology and tumor biology. The project also includes a rigorous graduate training plan to complement training in scientific research with didactics and training in scientific communication and teaching.