EZH2 Inhibition Boosts Tumor Immunogenicity and TIL Reactivity in Lung Cancer

Abstract

Lung cancer, the leading cause of cancer-related death in the United States, remains a significant public health burden. One of the most personalized treatments to date uses a patients own tumor-infiltrating lymphocytes (TILs) as a cellular therapy to target the tumor. Endogenous TIL activity is also essential for immune checkpoint inhibitor (ICI) effectiveness. However, responses to immunotherapies vary due to immune-suppressive tumor microenvironments (TMEs) and limited antigen presentation. In this study, we computationally examine cell-cell signaling and transcriptional activity using single-cell RNA sequencing of lung cancer treated by inhibiting methyltransferase EZH2. We show that EZH2 inhibition shifts the TME to immunogenic signaling patterns conducive to increased T cell response, including antigen presentation and homing. T cells also showed more stem-like phenotypes. Importantly, inferred EZH2 activity showed it can still perform non-methyltransferase duties that are vital for T cell differentiation. Lastly, we tested our findings with patient-derived NSCLC TILs and found that transient EZH1/2 inhibition with valemetostat prior to harvest increases the CD8:CD4 ratio and T cell reactivity, but preferentially expands effector memory rather than central memory populations. These results indicate that transitory EZH2 inhibition could improve immunotherapies for lung cancer patients, with additional optimization needed to maximize TIL therapeutic benefit.