Single-cell profiling of EZH2-mediated immune signaling perturbations in NSCLC

A bstract Lung cancer remains a significant public health burden. One of the most personalized treatments uses a patient’s own tumor infiltrating lymphocytes (TILs), and TIL activity is also essential for immune checkpoint inhibitor (ICI) effectiveness. 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. Transcriptional activity was quieter with EZH2 inhibition but revealed better interferon response, altered myeloid and B cell differentiation, and apoptotic markers. Importantly, inferred EZH2 activity showed it could perform non-methyltransferase duties vital for T cell differentiation. These results indicate that EZH2 inhibition could improve immunotherapies for lung cancer patients.