Cancer cell · 2025
EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models.
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Porazzi Patrizia, Nason Siena, Yang Ziqi, Carturan Alberto, Ghilardi Guido, Guruprasad Puneeth, Patel Ruchi P, Tan Melody, Padmanabhan Anushka Anant, Lemoine Jean, Fardella Eugenio, Zhang Yunlin, Pajarillo Raymone, Chen Linhui, Ugwuanyi Ositadimma, Markowitz Kelly, Delman Devora, Angelos Mathew G, Shestova Olga, Isshiki Yusuke, Blanchard Tatiana, Béguelin Wendy, Melnick Ari M, Linette Gerald P, Beatty Gregory L, Carreno Beatriz M, Cohen Ivan J, Paruzzo Luca, Schuster Stephen J, Ruella Marco
Аннотация
Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers' methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.