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1.
Nat Commun ; 15(1): 4327, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773088

RESUMO

The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.


Assuntos
Linfócitos T CD8-Positivos , Histona Desmetilases , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Camundongos , Humanos , Feminino , Camundongos Endogâmicos C57BL , Imunoterapia Adotiva/métodos , Linhagem Celular Tumoral , Ativação Linfocitária/efeitos dos fármacos , Transferência Adotiva , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Interleucina-2/metabolismo , Antígenos CD19/metabolismo , Antígenos CD19/imunologia , Memória Imunológica/efeitos dos fármacos
2.
Mol Cell ; 83(23): 4370-4385.e9, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38016475

RESUMO

Targeting epigenetic regulators to potentiate anti-PD-1 immunotherapy converges on the activation of type I interferon (IFN-I) response, mimicking cellular response to viral infection, but how its strength and duration are regulated to impact combination therapy efficacy remains largely unknown. Here, we show that mitochondrial CPT1A downregulation following viral infection restrains, while its induction by epigenetic perturbations sustains, a double-stranded RNA-activated IFN-I response. Mechanistically, CPT1A recruits the endoplasmic reticulum-localized ZDHHC4 to catalyze MAVS Cys79-palmitoylation, which promotes MAVS stabilization and activation by inhibiting K48- but facilitating K63-linked ubiquitination. Further elevation of CPT1A incrementally increases MAVS palmitoylation and amplifies the IFN-I response, which enhances control of viral infection and epigenetic perturbation-induced antitumor immunity. Moreover, CPT1A chemical inducers augment the therapeutic effect of combined epigenetic treatment with PD-1 blockade in refractory tumors. Our study identifies CPT1A as a stabilizer of MAVS activation, and its link to epigenetic perturbation can be exploited for cancer immunotherapy.


Assuntos
Interferon Tipo I , Viroses , Humanos , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Lipoilação , Epigênese Genética , Imunidade Inata
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