Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

Weng, R. R.; Lu, H.-H.; Lin, C.-T.; Fan, C.-C.; Lin, R.-S.; Huang, T.-C.; Lin, S.-Y.; Huang, Y.-J.; Juan, Y.-H.; Wu, Y.-C.; Hung, Z.-C.; Liu, C.; Lin, X.-H.; Hsieh, W.-C.; Chiu, T.-Y.; Liao, J.-C.; Chiu, Y.-L.; Chen, S.-Y.; Yu, C.-J.; Tsai, H.-C.

doi:10.1101/2020.04.30.069955

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bioRxiv · 10.1101/2020.04.30.069955

Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

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Abstract

{gamma}{delta} T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune systems and can attack cancer or virus-infected cells in an MHC-unrestricted manner. Despite its antitumor ability in both autologous and allogeneic settings, earlier trials of adoptive {gamma}{delta} T cell transfer in solid tumors had limited success due to limitations in cell expansion and the lack of a strategy to modulate tumor lytic interactions between {gamma}{delta} T and cancer cells. Here, we show through quantitative surface proteomics and gene enrichment analyses that DNA methyltransferase inhibitors (DNMTis) upregulate multiple surface molecules related to {gamma}{delta} T cell activation in cancer cells. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded {gamma}{delta} T cells using a clinical-grade expansion protocol developed by our team to enrich for the V{delta}1 subset while preserving their antitumor effector functions. Mechanistically, DNMTis enhance immune synapse formation and stabilize the synaptic cleft to facilitate {gamma}{delta} T-mediated tumor lysis. Through integrated analysis of RNA-seq, DNA methylation, and ATAC-seq, we demonstrate that depletion of DNMTs induces coordinated pattern alterations of immune synaptic-cytoskeletal networks at the cancer side of the immune synapse. In addition, single-cell mass cytometry reveals enrichment of polyfunctional {gamma}{delta} T subsets by DNMTis. Combined DNMTi and adoptive {gamma}{delta} T transfer in a mouse lung cancer model offers a significant survival benefit. Consistently, the DNMTi-associated cytoskeleton signature identifies a subset of lung cancer patients with improved survival. Our results demonstrate that epigenetic mechanisms are crucial for cytoskeletal remodeling in cancer to potentiate immune attack and support a combinatorial strategy of DNMTis and {gamma}{delta} T cell-based immunotherapy in lung cancer management. One Sentence SummaryDNA methyltransferase inhibitors potentiate the killing of lung cancer by {gamma}{delta} T cells through remodeling cytoskeletal-immune synaptic networks.

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Weng, R. R., Lu, H.-H., Lin, C.-T., Fan, C.-C., Lin, R.-S., Huang, T.-C., Lin, S.-Y., Huang, Y.-J., Juan, Y.-H., Wu, Y.-C., Hung, Z.-C., Liu, C., Lin, X.-H., Hsieh, W.-C., Chiu, T.-Y., Liao, J.-C., Chiu, Y.-L., Chen, S.-Y., Yu, C.-J., Tsai, H.-C.. 2020-05-02. Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells. https://doi.org/10.1101/2020.04.30.069955

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