Dissecting the Myeloid-Th17 axis in the pathogenesis of Colitis-associated Colorectal Cancer

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Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality in the United States. Chronic intestinal inflammation is a major risk factor for the development and progression of sporadic and colitis- associated colorectal cancer (CAC). While the pathogenic effects of tumor-promoting inflammation are widely recognized, the mechanisms driving this process, including the cellular and molecular mediators are poorly understood. This has therapeutic implications especially in CRC where the currently available T-cell checkpoint inhibitors have a limited benefit. In preliminary studies, we used the azoxymethane/ dextran sulfate sodium model of inflammation-driven colon carcinogenesis that allows interrogation of the initiation-promotion events underpinning the development of CAC. We observed that compared to the surrounding non-tumor-bearing colon, the tumor microenvironment is enriched with tumor-infiltrating myeloid (TIM) cells, including neutrophils (PMNs), monocytes, and tumor-associated macrophages (TAMs). PMNs are the predominant population and are recruited through the Cxc-Cxcr2 axis while the monocytes/TAMs (M) appear to rely on the Cc-Ccr2 pathway. Both subsets express pro-inflammatory and immune-suppressive genes thereby suggesting their pro- tumorigenic role. Additionally, the tumor microenvironment has an increased abundance of interleukin (IL)-17 producing CD4+ T (Th17) and gamma-delta T cells. IL-17 is a pro-inflammatory cytokine that promotes CRC growth and increased expression is associated with poor prognosis. Previous studies indicate that TIMs promote Th17 development through the production of IL-23 (IL-23A/IL-12B heterodimer). However, our single-cell RNA sequencing studies revealed that while the PMNs expressed Il23a, they did not express Il12b thereby suggesting an inability to produce functional IL-23. Instead, the PMNs expressed Epstein-Barr virus-induced gene 3 (Ebi3) which has recently been shown to dimerize with IL-23A to form IL-39, a pro-inflammatory cytokine. We hypothesize that the myeloid-Th17 axis is critical for the maintenance of an inflammatory microenvironment that helps sustain CAC progression. We propose the existence of a feed-forward loop in the tumor microenvironment whereby the PMNs and M work synergistically to promote Th17 development, and the resulting IL-17, in turn, recruits and maintains more PMNs and M in the tumor thereby reinforcing an inflammatory microenvironment which fuels CAC progression. Mechanisms to disrupt this loop will be the focus of our proposal. Our first aim will attempt to define the role of TIMs in the pathogenesis of CAC by exploring the effects of blocking colonic recruitment of PMNs and M on tumor development (Aim IA) or their deletion in established tumors (Aim IB). In our second aim, we will explore the role of IL-39 as an alternative mechanism of Th17 development (Aim IIA) and assess its role in tumor development (Aim IIB), including the effects of cell-specific deletion of the Ebi3 in PMNs and CD4+T cells (Aim IIC). These studies will have implications in treatment strategies for patients with CAC and other immune-mediated diseases like inflammatory bowel disease.