Defining the role of eosinophils in the development of esophageal malignancy

About This Grant

Background and Innovation: Worldwide, Esophageal squamous cell carcinoma (ESCC) accounts for 85% of the incident 604,100 esophageal cancer cases. Median survival from diagnosis in patients with ESCC is a meager 10 months. Making matters worse, recurrent disease is common, with reported rates as high as 30-50%. Moreover, even in patients with localized disease where the combination of chemoradiotherapy and esophagectomy has led to a modest increase in median survival in recent years, there is often decreased health related quality of life, continued eating difficulties, malnutrition, and poor long-term survival. Thus, new therapeutic strategies and approaches are needed to manage ESCC. In order to address this need, immunotherapies which prevent cancers from evading the immune system have recently been approved for treatment of esophageal cancer. However, these therapies focus on T cells and only increase survival by 2-3 months. Our proposal focuses on eosinophils, another immune cell, which we have discovered is protective in the development of ESCC. Our data reveal that eosinophils are present in greater numbers in the early stages of human ESCC and the 4-NQO murine model of ESCC. Through the support of my VA Career Development Award, we demonstrated that eosinophils played a protective role in the development of ESCC in several mouse models. Genetically eosinophil-deficient (DdblGATA) mice, mice treated with an anti-IL5 monoclonal antibody, which blocks eosinophil production, and Ccl11-/- mice, lacking eotaxin-1, a key eosinophil chemoattractant, all exhibit significantly worse tumorigenesis after 4-NQO. Conversely, treatment of mice with intranasal recombinant IL-5 (rIL-5), which enhances esophageal eosinophilia, reduced ESCC tumorigenesis, providing evidence that increasing eosinophil recruitment has therapeutic potential in ESCC. Mechanistically, we are beginning to understand that the release of reactive oxygen species (ROS) during eosinophil degranulation is one way which eosinophils induce death of surrounding pre-cancer and cancer cells. We have also observed that eosinophils can modify the T cell composition of the neoplastic environment, as there are more CD4 T cells in the absence of eosinophils and fewer after treatment with rIL-5. We have demonstrated that that these CD4 T cells are likely Th17 cells, and given that chronic IL-17 is pro-tumorigenic, eosinophils may also be protective by suppressing Th17 signaling. Building on these data, we have proposed innovative studies to further elucidate the protective role of eosinophils in ESCC. In Specific Aim 1, we will define the contributions of the predominant eosinophilic ROS, hypobromous acid (HOBr) and hydrogen peroxide (H2O2), to the protective effect of eosinophils in ESCC. In Specific Aim 2, we will determine whether eosinophils are protective through suppression of IL-17 signaling [and identify other immune cells which are significantly altered by eosinophils.] Significance and Impact to Veterans’ Healthcare: Out of all Veterans with esophageal cancer between 1995- 2005, 44% (3,493) were ESCC. Between 2000-2020, our data reveals that there were at least 6,427 cases of ESCC in VHA. At diagnosis, 60-91% of Veterans had at least Stage II disease, with 26% presenting with metastatic disease. Median survival was only 7.3 months after diagnosis. Given that ESCC carries such a poor prognosis, our studies have the potential to have tremendous impact for Veterans with ESCC. Path to Translation/Implementation: We have identified a number of therapeutic targets based on prior CDA-2 studies. In Specific Aim 2, we will test whether a monoclonal antibody to IL-17A can attenuate ESCC tumorigenesis. In Specific Aim 3, we will determine the therapeutic potential [of current immunotherapy] combined with enhanced eosinophil recruitment with recombinant CCL11 or recombinant IL-5 in the 4-NQO murine pre-clinical model. Thus, there are several potential therapeutic agents which could result directly from this proposal. Overall, we will gain fundamental insights into how eosinophils are protective directly and indirectly in the progression of ESCC, informing the development of new therapeutics for Veterans.