Targeting tumor innate immune signaling in pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Effective treatment remains an unmet and urgent need for patients with pancreatic ductal adenocarcinoma (PDAC). Unlike most cancer types where targeted therapies and immunotherapy have become standard treatments, PDAC is unique among major cancers in still relying almost entirely on chemotherapy for disease control. The administration of multiple cytotoxic agents, while necessary for efficacy, results in significant clinical toxicities, and treatment response rates remain low at 30–40%, with responses often lacking durability. Therefore, achieving therapeutic breakthroughs necessitates novel biological discoveries in pancreatic cancer. Over the past decade, our lab has generated substantial preclinical and clinical evidence showing that innate immune signaling pathways in PDAC cells are critical in establishing an immunosuppressive tumor microenvironment that inhibits anti-tumor T cell activity. We initially focused on IRAK4, a kinase regulating Toll-like receptor and IL-1 receptor signaling and demonstrated that targeting IRAK4 enhances chemotherapy efficacy and may potentiate immunotherapy. This work laid the groundwork for three clinical trials. Building on these insights, we have identified additional signaling nodes related to IRAK4, with MAP3K8 (TPL2) emerging as a particularly promising target. Our preliminary data indicate that TPL2 regulates multiple signaling pathways in PDAC cells, including the processing of micro(mi)-RNA species that may endow these cells with aggressive and immunosuppressive phenotypes. We found that targeting TPL2 enhances the efficacy of FOLFIRINOX chemotherapy and reprograms the tumor microenvironment, potentially enabling checkpoint immunotherapy to be effective in PDAC. Based on these findings, our team proposes three Aims: Aim 1: We will investigate the mechanism by which TPL2 controls miRNA processing, particularly through modulation of AGO2 and AGO3 function. This study will provide one of the few comprehensive analyses of miRNA's role in PDAC biology. To ensure success, we will collaborate with an experienced RNA biologist, Dr. Sergej Djunarovic. Aim 2: We will explore the role of TPL2 in PDAC cells, as well as in myeloid and T cells, using a conditional TPL2 knockout mouse strain provided by Dr. Andrew Greenberg. These experiments will elucidate how TPL2 influences PDAC tumor progression and inform immunotherapeutic strategies tested in Aim 3. Aim 3: We will evaluate the preclinical efficacy of the TPL2 inhibitor tilpisertib combined with FOLFIRINOX in 20 patient-derived xenograft models. We will also identify a rational immunotherapeutic combination to be tested in the immunocompetent genetic (KPPC) mouse model.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Our proposal seeks to elucidate the mechanisms by which MAP3K8, or TPL2 kinase, influences tumor-intrinsic signaling and the immune microenvironment in pancreatic cancer. We will leverage a novel genetic mouse model, state-of-the-art technologies, and a pharmacological approach to address these questions. Our research aims to uncover the unique biology of TPL2 signaling in both immune and pancreatic cancer cells and rigorously evaluate the efficacy of TPL2 inhibitors in combination with chemotherapy and immunotherapy. Ultimately, our goal is to advance novel therapeutic strategies to the clinic for the benefit of pancreatic cancer patients.