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Single-cell profiling of EZH2-mediated immune signaling perturbations in NSCLC
Daniel R Plaugher1, Avery R Childress1, Christian M Gosser1
1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY 40536 USA.
Abstract:
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.
Insights
Inhibiting EZH2 in lung cancer promotes a more immune-friendly tumor microenvironment, enhancing T cell responses and potentially improving immunotherapy effectiveness for patients.
Area of Science:
- Oncology
- Immunology
- Computational Biology
Background:
- Lung cancer is a major public health concern with limited treatment options.
- Tumor-infiltrating lymphocytes (TILs) and immune checkpoint inhibitors (ICIs) are personalized lung cancer treatments.
- Immune-suppressive tumor microenvironments (TMEs) and poor antigen presentation hinder immunotherapy efficacy.
Purpose of the Study:
- To computationally investigate the effects of EZH2 inhibition on the lung cancer TME.
- To analyze cell-cell signaling and transcriptional changes induced by EZH2 inhibition.
- To determine the potential of EZH2 inhibition in enhancing lung cancer immunotherapies.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed to analyze lung cancer tissues.
- Computational methods were used to examine cell-cell signaling and transcriptional activity.
- Inferred EZH2 activity was analyzed for its role in T cell differentiation.
Main Results:
- EZH2 inhibition reprogrammed the TME towards immunogenic signaling, improving T cell antigen presentation and homing.
- T cells exhibited enhanced stem-like phenotypes following EZH2 inhibition.
- Transcriptional analysis revealed increased interferon response, altered myeloid and B cell differentiation, and apoptotic markers.
- EZH2 was found to have non-methyltransferase functions crucial for T cell differentiation.
Conclusions:
- EZH2 inhibition shifts the lung cancer TME to an immunogenic state, supporting T cell responses.
- EZH2 inhibition may enhance the effectiveness of current immunotherapies for lung cancer.
- EZH2 possesses non-enzymatic functions vital for T cell development, offering new therapeutic avenues.
