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Rodrigues Carvalho, Maria Leticia
;
de Oliveira Andrade, Clara
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Cabral-Piccin, Mariela Pires
;
Kinker, Gabriela Sarti
;
Vitiello, Glauco Akelinghton Freire
;
Goncalves Cambui, Raylane Adrielle
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de Macedo Abdo, Luiza
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Mannarino Correia, Eduardo
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da Silva Elias, Bruno Dalbelo
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Araujo, Emmanuel Vinicius Oliveira
;
Chaves, Alexandre Silva
;
Pereira, Pedro Henrique Barbosa
;
Hajdu, Karina Lobo
;
Rondinelli, Amanda
;
Fagotti Gusmao, Arianne
;
Marques Pierre, Maria Luisa
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Brasil-Costa, Igor
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Pouza Zanella, Caroline
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Moreira Lemos, Marta Maria
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Batista, Marjorie Vieira
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Filho, Jayr Schmidt
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Arrowsmith, Cheryl
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Cordeiro de Lima, Vladmir Claudio
;
Bonamino, Martin Hernan
;
da Silva Medina, Tiago
Número total de Autores: 25
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| Tipo de documento: | Artigo Científico |
| Fonte: | Cancer Research; v. 85, n. 12, p. 16-pg., 2025-06-16. |
| Resumo | |
Chimeric antigen receptor (CAR) T-cell therapy is increasingly being adopted as a clinical modality for patients with relapsed/refractory hematologic malignancies. Despite the clinical efficacy of CAR T-cell therapy, a considerable fraction of patients still relapse during the first months following CAR T-cell infusion. The limited CAR T-cell efficiency is thought to relate to epigenetic mechanisms involved in T-cell suppression and dysfunction. In this study, screening of multiple epigenetic inhibitors revealed that targeting polycomb repressive complex 2 (PRC2) consistently induced the development of granzyme B+ effector memory CD8 T cells. Notably, PRC2 inhibition also promoted the long-term persistence of granzyme B+ effector memory 19BB zeta CAR T cells and enhanced sustainably their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BB zeta CAR T cells did not exhibit signs of exhaustion over time. Furthermore, TCR restimulation along with PRC2 inhibition promoted the differentiation of patient-derived anti-CD19 effector memory CAR T cells with enhanced cytotoxic features and elicited potent antitumor responses. In line with this, the gene signature derived from in-house PRC2-inhibited 19BB zeta CAR T cells was enriched in tisagenlecleucel BB zeta CAR T-cell therapy responders with large B-cell lymphoma. Collectively, our results demonstrated that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR T cells against hematologic malignancies.Significance: Selective inhibition of PRC2 endows 19BB zeta CAR T cells with cytotoxic and effector memory features that are associated with improved antitumor activity and better response to CAR T-cell therapy. (AU) | |
| Processo FAPESP: | 22/00747-8 - Avaliação do potencial antitumoral de células T CD39+ em pacientes com carcinoma renal de células claras |
| Beneficiário: | Emmanuel Vinicius Oliveira Araujo |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 20/10299-7 - PIWIL4 como regulador epigenético central de elementos retrovirais endógenos no Câncer Gástrico: implicações na imunopatogênese e imunoterapia da doença? |
| Beneficiário: | Glauco Akelinghton Freire Vitiello |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 19/25129-2 - Caracterização detalhada das células T em Adenocarcinomas Ductais Pancreáticos |
| Beneficiário: | Gabriela Sarti Kinker |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 14/50943-1 - INCT 2014: de Oncogenômica e Inovação Terapêutica |
| Beneficiário: | Dirce Maria Carraro |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 18/14034-8 - Caracterização dos perfis da cromatina e transcricional de células T de pacientes com adenocarcinoma gástrico como estratégia para o descobrimento de alvos imunoterapêuticos |
| Beneficiário: | Tiago da Silva Medina |
| Modalidade de apoio: | Auxílio à Pesquisa - Jovens Pesquisadores |
| Processo FAPESP: | 21/00643-5 - Caracterização dos perfis da cromatina e transcricional de células T de pacientes com adenocarcinoma gástrico como estratégia para o descobrimento de alvos imunoterapêuticos |
| Beneficiário: | Maria Letícia Rodrigues Carvalho |
| Modalidade de apoio: | Bolsas no Brasil - Mestrado |