Saturday, December 21, 2024
12/21/2024
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 24-044. Uterine serous carcinomas (USC) represent 10% of endometrial cancers (EC) but account for nearly 40% of deaths from the disease. This disproportionate difference between incidence and death emphasizes the need to improve treatment strategies. One new potential therapeutical approach is the immunotherapy which can induce a dramatic and durable tumor regression across several cancer types, including other subtypes of EC, but has yet to have success in the treatment of USC. Characterization of the immune tumor microenvironment (TME) is a prerequisite for the selection of the optimal immunotherapy combinations. Emerging data show that USC tissues are characterized by a high number of myeloid cells, including M2-like tumor associated macrophages (TAM) and granulocytic myeloid derived suppressor cells (G-MDSC). However, little is known about the tumor secreted factors that induce the TAM and G-MDSC recruitment and modulate their functional activities in USC. We have identified EGFL6 (EGF like domain multiple 6) as a new factor regulating the recruitment and functions of TAM and G-MDSC in the HGSOC and potentially the USC TME. Egfl6 is highly expressed in uterine cancer, including USC. Mice overexpressing Egfl6 have an increased numbers of bone marrow (BM) G-MDSC and develop spontaneous tumors in the uterus. Treatment with recombinant protein Egfl6 of BM derived myeloid cells was associated with an increase Syk activation and promoted differentiation of G-MDSCs towards an immunosuppressive phenotype. Moreover, tumor expression of Egfl6 enhanced tumor growth and increased tumor infiltration of G-MDSC and M2-like TAM. Furthermore, combined treatment of a-Egfl6 and a-PD-L1 reduced numbers of pro-tumorigenic TAM and G-MDSC resulting in survival rate prolongation of serous ovarian cancer bearing mice. Furthermore, SYK is highly expressed in human USC tissue samples. We hypothesize that Egfl6, via Syk activation, induces the recruitment of TAM and G-MDSC and enhances their immunosuppressive phenotype resulting in the inhibition of anti-tumor immune response. To test our hypothesis, we propose: SA1. To determine the role of Egfl6/Syk axis in TAM and G-MDSC infiltrating USC. Using a syngeneic mouse model of USC, we will use R788, a potent Syk inhibitor, to determine the role of Syk in the Egfl6-dependent regulatory axis controlling TAM and G-MDSC. We will also evaluate the impact of a- Egfl6 or R788 in combination with a-PDL1 on anti-tumor immunity in USC. SA2. To evaluate Egfl6 expression and the immune TME in USC patients. The characterization of the immune TME can help to make substantial progress in the identification of the likelihood of response to immunotherapies. We will evaluate 1) EGFL6 and SYK expression, and 2) the abundance and phenotype of tumor infiltrating immune cells. Because USC is more common in Black vs White women, we will also compare the immune USC TME of Black vs White Women.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).