Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer

gamma delta 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 gamma delta 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 gamma delta T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded V delta 1-enriched gamma delta 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 gamma delta T cell-based immunotherapy in lung cancer management. Gamma delta (gamma delta) T cells have potential for use in immunotherapy against tumours. Here, the authors demonstrate that treatment of tumours with DNA methyltransferase inhibitors modulates cytoskeleton arrangements, upregulates adhesion molecules and increases tumour killing by gamma delta T cells.

Automated summary

Gamma delta T cells are a subtype of T cells that can bridge the gap between the innate and adaptive immune system by attacking cancer cells in an MHC-unrestricted manner. Treatment of solid tumors with DNA methyltransferase inhibitors has been shown to enhance tumor cell susceptibility to gamma delta T cell killing through the upregulation of surface molecules and modulation of cytoskeleton arrangements. This combinatorial approach holds promise for lung cancer management by utilizing DNMTis and gamma delta T cell-based immunotherapy.