Project 2: Inter-Relationship of Disparities, the Microbiome, Innate Immune System and Immunotherapy Response in Endometrial Cancer

ABSTRACT – PROJECT 2 Endometrial cancer (EC) outcomes are among the most disparate in the US, with Black women suffering a much lower 5-year survival rate than White women. Reasons for this are unclear but likely include an inter-relationship between measurable social factors and biology, including potentially differences in the microbiome and the immune system. Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) provides significant clinical benefit in patients with EC. Two critical and inter-related factors that impact IO benefit are (1) the gut and tumoral microbiome, and (2) the innate immune system (IIS) which is responsible for uptake and clearance of monoclonal antibodies (mAbs), such as PD-1 inhibitors. We were the first to evaluate differences in the microbiota of ECs, with the discovery that distinct microbiota profiles differentiated ECs of Black vs White women. Furthermore, our preliminary studies show that Black patients have a heightened IIS, which may result in lower exposures of mAbs due to enhanced clearance of the mAbs by the IIS; and thus, Black women may need higher doses of mAbs (such as PD-1 inhibitors) to achieve the same optimal therapeutic response as White women. Thus, we hypothesize that differences exist in the tumor/gut microbiome and the IIS of Black women that will culminate in lower IO response and worse survival. Using an ongoing North Carolina population-based study (Carolina Endometrial Cancer Study [CECS]) and a prospective study of UNC EC patients undergoing PD-1 inhibitor therapy (PROMOTE), we will evaluate the EC tumoral and gut microbiota and the IIS in Black and White patients in relationship to measurable social factors, treatment response and survival outcomes. We will also perform more mechanistic studies in a unique germfree EC mouse model studying fecal microbial transplant (FMT) as a means to improve PD-1 inhibitor` treatment response. This work will lead to the development of microbiota-directed interventions (i.e., FMT) to manipulate bacterial presence and resolve microbial dysbiosis to improve PD-1 inhibitor efficacy and other clinical outcomes in EC patients. In addition, the dose of PD-1 inhibitor treatment may need to be increased to optimize therapy in women based on their IIS profiles. Ultimately this work will identify future actionable microbial and immune factors and targets for improving outcomes and disparities in EC to be explored in subsequent clinical trials.