Abstract
γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.
Highlights
Γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an major histocompatibility complex (MHC)-unrestricted manner
DNA methyltransferase inhibitors (DNMTis) have been shown to modulate pathways related to antigen processing/presentation, human leukocyte antigens (HLA), and interferon responses across different cancer types at the transcriptomic level[11,12]
We sought to obtain a comprehensive profile of surface proteins altered by decitabine (DAC) through isolating cell surface proteins from A549 human lung cancer cells before and after DAC treatment using the EZ-link Sulfo-NHS-SSbiotin-assisted biotinylation method, followed by a SILAC-based quantitative proteomics approach (Fig. 1a)[14]
Summary
Γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Γδ T cells, a distinct subset of T cells that sense molecular stress signals from pathogen-infected or transformed cells, can display broad tumor-targeting capabilities in a major histocompatibility complex (MHC)-independent manner[4] These cells provide potential therapeutic opportunities for patients who are inherently unresponsive to checkpoint blockade due to low mutational burden, or have acquired defects along the TCR-MHC axis. We show that DNMTis markedly alter the surface proteome of lung cancer cells using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics These experiments show upregulation of multiple MHCunrestricted immune recognition molecules following transient DNMTi treatment at low doses. Primary lung cancer tissues can be stratified by immune cytoskeleton patterns indicative of responses to γδ T-mediated cytotoxicity, which may aid in patient selection in future clinical trials for precision immunotherapy These findings support the broad applicability of DNMTis in remodeling the cancer cell cytoskeleton for MHCunrestricted γδ T cell-based therapy
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