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EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models
Patrizia Porazzi1, Siena Nason1, Ziqi Yang1
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
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.
Insights
Inhibiting EZH1/2 methyltransferases reprograms tumors to be more immunogenic, enhancing chimeric antigen receptor T-cell (CAR-T) therapy efficacy. This approach potentiates adoptive cell immunotherapy in preclinical models of various cancers.
Area of Science:
- Immunology
- Oncology
- Epigenetics
Background:
- Tumor resistance to chimeric antigen receptor T-cell (CAR-T) and adoptive cell immunotherapies (ACTs) is a significant clinical hurdle.
- Epigenetic modifications, specifically methyltransferase activity, play a role in cancer immune evasion.
Purpose of the Study:
- To investigate if inhibiting EZH2 and EZH1 methyltransferases can enhance CAR-T cell therapy efficacy.
- To determine if EZH1/2 inhibition reprograms tumors towards a more immunogenic state, improving ACT outcomes.
Main Methods:
- Utilized EZH2 inhibitor (tazemetostat) and combined EZH1/EZH2 inhibitor (valemetostat) in preclinical cancer models.
- Assessed CAR-T cell activation, expansion, tumor infiltration, and overall efficacy in various liquid and solid cancers.
- Analyzed gene expression changes related to immune response and tumor cell avidity.
Main Results:
- EZH2 inhibition with tazemetostat improved anti-CD19 CAR-T efficacy in B cell lymphoma by enhancing T-cell function and tumor infiltration.
- Tazemetostat treatment led to upregulation of adhesion, B cell activation, and inflammatory response genes, increasing CAR-T avidity.
- Combined EZH1/EZH2 inhibition with valemetostat further boosted CAR-T efficacy and expansion across multiple cancer types.
Conclusions:
- EZH1/2 inhibition effectively reprograms tumors into a more immunogenic phenotype.
- Targeting EZH1/2 represents a promising strategy to overcome resistance and enhance the efficacy of CAR-T and other ACTs in diverse cancers.
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