Epigenetic Priming of Bladder Cancer Cells to Enhance CAR T-cell Mediated Cytotoxicity – Expert Commentary

CD19-directed chimeric antigen receptor (CAR) T cells are now used to treat B-cell malignancies. Extending their use to solid tumors requires optimizing the interactions between CAR-T cells and specific cancer cell types. A recent study by Grunewald et al. examined the role of DNA methyltransferases inhibitors (DNMTi) and histone deacetylases inhibitors (HDACi) to optimize improving CAR-T cell-mediated tumor-specific cytotoxicity against bladder cancer cells.


The investigators examined the effect of co-incubating CAR-T cells directed against EGFR or CD44v6 with a panel of urothelial carcinoma cell lines (UCC) and benign uroepithelial HBLAK cells. Cytotoxicity assays were used as readouts. The impact of DNMTi and HDACi treatments on the transcriptome of UCC was examined by RNA sequencing.

The investigators found that the CAR Target Antigens EGFR and CD44v6 were expressed on the surface of UCCs.  The DNMTi and Decitabine, but not the HDACi romidepsin, increased CAR T-cell mediated cytotoxicity against all UCC lines, but not against the benign HBLAK cells. Interestingly, drug-induced alterations in the T-cell ligands PD-L1, PD-L2, ICAM-1, or CD95 did not adequately account for CAR T-cell-mediated cytotoxicity differences. Decitabine resulted in a pro-apoptotic profile associated with higher CAR T-cell mediated cytotoxicity. On the other hand, romidepsin resulted in an anti-apoptotic profile. Confirming this hypothesis, the investigators found that knocking down components of crucial apoptosis regulators such BID and BCL2L1/BCLX UCC altered their sensitivity to CAR-T cell-mediated tumor-specific cytotoxicity.

This study highlights the role of epigenetic priming and targeting anti-apoptotic proteins for enhancing CAR T-cell mediated cytotoxicity.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Grunewald CM, Haist C, König C, Petzsch P, Bister A, Nößner E, Wiek C, Scheckenbach K, Köhrer K, Niegisch G, Hanenberg H, Hoffmann MJ. Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells. Front Immunol. 2021 Nov 17;12:782448. doi: 10.3389/fimmu.2021.782448. eCollection 2021. PMID: 34868059

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