Dissecting the Source and Mechanisms of IL-17-Mediated Modulation of Pancreatic Tumorigenesis

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

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Abstract

Abstract The incidence of pancreatic adenocarcinoma (PDAC) is steadily increasing while most treatment modalities remain ineffective. Therefore, it would not be a surprise to learn that PDAC is one of the top-4 causes of cancer- related mortality. What is most striking about this malignancy is that even if detected at early stages, outcomes remain poor. It is well known that pancreatic cancer is characterized by an immunosuppressive environment, already found surrounding premalignant lesions or pancreatic intraepithelial neoplasia (PanIN), which has been postulated as one of the main reasons for the lack of response to most therapies. However, the regulatory signals that precede and support the development of this suppressive TME are not well characterized. The objective of this grant extension is to characterize the gut cellular compartments and mechanisms implicated in the intestinal IL-17 signaling dependent regulation of the gut microbiome and tumor growth and potential avenues to reverse it through immune checkpoint blockade and microbial interventions. Our laboratory found that IL- 17-secreting immune cells play an important role in promoting pancreatic tumorigenesis in genetically engineered mouse (GEMM) models of pancreatic cancer. Further, we revealed IL-17-IL-17RA signaling specific to the gut epithelium plays a key role in modulating tumor growth through microbial regulation. We now plan to characterize the cellular compartment within the intestinal epithelium responsible for modulating IL-17/IL-17RA mechanisms. GEMM models with specific IL-17RA deletion in Intestinal Stem Cells and Secretory Progenitor cells will be used to assess the cellular compartment regulating IL-17 effects (Aim 4). Finally, we have recently found that mice with global elimination of B7H4 presented higher CD8+ T cells pancreatic infiltration and, when using therapeutic antibodies blocking B7H4 in combination with aPD1 immunotherapy in PDAC orthotopic models, a strong immune remodeling occurred. We now plan to definitively address the therapeutic effect of B7H4 inhibition alone and in combination with immune checkpoint blockade in PDAC (Aim 5). Achieving our goals will not only help us better understand immunological as well as microbial mechanisms implicated in pancreatic tumorigenesis but will also result in practical novel interventions with either monoclonal antibodies, narrow spectrum antibiotics or microbial transplants that would have a direct impact in preventing and/or treating this deadly disease.