Pfn1’s Role in Genomic Stability and Immune Response in Breast Cancer

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Project Summary Breast cancer is the second leading cause of cancer related deaths in women in the United States Immune checkpoint blockade immunotherapy is an emerging treatment for breast cancer, particularly for triple-negative breast cancer which lacks targeted therapies. Immune checkpoint blockade failure is often due to immune- excluded tumor microenvironments, specifically the absence of CD8+ T cell infiltration. Currently immune checkpoint blockade agents are used in combination with conventional chemotherapies which enhance the function of immunotherapy by inducing DNA damage a trigger for an anti-tumor immunological response. However, tumors are known to become resistant to chemotherapies, therefore identification of novel mechanisms to induce DNA damage and thus CD8+ T cell infiltration is key for improving immune checkpoint blockade immunotherapy success. Profilin-1 (Pfn1) is an actin-binding protein that has been reported to have context dependent tumor intrinsic roles in breast cancer. While overexpression of Pfn1 has been shown to suppress tumorigenesis, knockdown of Pfn1 has been demonstrated to limit metastatic outgrowth. However, the impact of Pfn1 modulation on the tumor immune microenvironment in breast cancer remains uninvestigated. My preliminary data suggests genetic disruption of the Pfn1 gene leads to an increase in CD8+ T cell infiltration and significant tumor regression. The goal of this project is to investigate whether and how loss of Pfn1 causes a pro-inflammatory, anti-tumor microenvironment thereby increasing immunotherapy efficacy. The proposed research will be complemented by a training plan I designed to achieve the aims of this project and prepare myself for the next phase of my research career. My undergraduate and early graduate school research focused on molecular mechanisms of cancer cell migration and tumor biology. During the F31 fellowship period I will extend my understanding of cancer to the tumor immune microenvironment and immunotherapy treatment. I will learn technical skills including how to perform flow cytometry analysis, immunotherapy administration, and microfluidic device fabrication. I will build upon my skills in the design of rigorous scientific approaches, mentorship, and outreach.