Lung cancer is the leading cause of cancer deaths globally. While immunotherapy has improved survival rates, many tumors don't respond due to mutations that can lead to poor treatment outcomes. In this project, Dr. Woodard will investigate how T cells are prevented from entering tumors with specific mutations and explore ways to enhance T cell migration to improve immunotherapy response. She will focus on PLA2G10, a protein that blocks T cell entry into lung tumors, examining how it prevents CD4+ and CD8+ T cell migration and its relationship with common lung cancer mutations. The goal is to understand and improve T cell exclusion mechanisms to make immunotherapy more effective.
- Research Summary
Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Immunotherapy has led to dramatic improvements in survival, but not all tumors respond with certain mutations predicting a poor immunotherapy response. This award will test a hypothesis of how T cells are excluded from tumors with certain mutations and study how to improve T cell migration into tumors as a way to improve tumor response to immunotherapy. PLA2G10 is a protein that mediates T cell exclusion from lung tumors, we will study how this protein prevents migration of CD4+ and CD8+ T cells and we will study its association with common lung cancer mutations.
- Technical Abstract
NSCLC is the leading cause of cancer related mortality in the United States and worldwide. Immune checkpoint inhibitors that target the programmed cell death-ligand 1 (PD-L1) pathway have revolutionized the outcomes of NSCLC; however, only a minority of patients obtain clinical benefit from immunotherapy. PLA2G10 is a protein that mediates T-cell exclusion by inhibiting migration of CD4+ and CD8+ T-cells and its association with common lung cancer mutations is unknown. Lung cancer mutations such as tumor suppressor gene Serine/threonine kinase 11 (STK11), are associated with decreased immune cell infiltration into the tumor and associated with immunotherapy resistance.
The proposed project will utilize the resources of the Yale Lung SPORE BioRepository of treatment naïve and immunotherapy treated surgically resected, stage I-III NSCLC tumor samples. We will then study the immune tumor immune microenvironment in relation to PLA2G10 overexpression in tumors with and without STK11 mutations (Aim 1). The impact of STK11 mutations and PLA2G10 will then be studied on T-cell migration in lung cancer cell lines (Aim 2). Our hypothesis is that PLA2G10 expression is a driving mechanism for T cell exclusion observed in STK11mut tumors. We propose to demonstrate that inhibition of PLA2G10 in STK11mut cell lines will improve T-cell migration and sensitize tumors to immunotherapy. Thus, we will explore PLA2G10 as a novel therapeutic target in immunologically cold tumors and future applications of this research would be to study drug combinations that overcome T-cell exclusion as an immunotherapy resistance mechanism.