American Association for Cancer Research
cd-22-1350_supplementary_figures_s1-s8_suppsf1-sf8.docx (7.51 MB)

Supplementary Figures S1-S8 from SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors

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journal contribution
posted on 2024-01-12, 08:21 authored by Sheila López-Cobo, Jaime R. Fuentealba, Paul Gueguen, Pierre-Emmanuel Bonté, Kyriaki Tsalkitzi, Irena Chacón, Salomé Glauzy, Armelle Bohineust, Ariane Biquand, Lisseth Silva, Zelia Gouveia, Christel Goudot, Franck Perez, Michael Saitakis, Sebastian Amigorena

Supplementary Figures and Legends, Supplementary Table Legends Supplementary Figure S1.Engineering SUV39H1-deficient human T cells. Supplementary Figure S2. SUV39H1-deficient T cells show enhanced stem/memory and less effector/exhausted phenotype. Supplementary Figure S3. SUV39H1 deletion in CAR T cells promotes stronger rejection of liquid and solid tumors. Supplementary Figure S4. Single-cell transcriptomics reveals enrichment of stem/memory cells and signatures in SUV39H1-deficient CAR T cells. Supplementary Figure S5. Enhanced self-renewal in SUV39H1-deficient stem/memory populations. Supplementary Figure 6. SUV39H1-deficient memory CAR T cell signature correlates with clinical response. Supplementary Figure 7. SUV39H1 ablation induces chromatin opening at stem/memory loci in all CAR T cell subpopulations. Supplementary Figure 8. SUV39H1-deficient BBz-CAR T cells show stronger memory persistence and mediate long-term protection against tumor rechallenge.


Agence Nationale de la Recherche (ANR)

Institut Curie



Failure of adoptive T-cell therapies in patients with cancer is linked to limited T-cell expansion and persistence, even in memory-prone 41BB-(BBz)–based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T-cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 trimethylation (H3K9me3) pathway. Inactivation of the H3K9 trimethyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T-cell infusion. Single-cell transcriptomic (single-cell RNA sequencing) and chromatin opening (single-cell assay for transposase accessible chromatin) analyses of tumor-infiltrating CAR T cells show early reprogramming into self-renewing, stemlike populations with decreased expression of dysfunction genes in all T-cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes the long-term functional persistence of BBz-CAR T cells, limiting relapses, and providing protection against tumor rechallenges. Limited CAR T-cell expansion and persistence hinders therapeutic responses in solid cancer patients. We show that targeting SUV39H1 histone methyltransferase enhances 41BB-based CAR T-cell long-term protection against tumor relapses and rechallenges by increasing stemness/memory differentiation. This opens a safe path to enhancing adoptive cell therapies for solid tumors.See related article by Jain et al., p. 142.This article is featured in Selected Articles from This Issue, p. 5

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