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PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer.
Panahi Meymandi, Ahmad Reza; Akbari, Behnia; Soltantoyeh, Tahereh; Shahosseini, Zahra; Hosseini, Mina; Hadjati, Jamshid; Mirzaei, Hamid Reza.
Afiliación
  • Panahi Meymandi AR; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Akbari B; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Soltantoyeh T; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Shahosseini Z; Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
  • Hosseini M; Virology Department, Pasteur Institute of Iran, Tehran, Iran.
  • Hadjati J; Department of Pharmaceutical Biotechnology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Mirzaei HR; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Front Oncol ; 14: 1357801, 2024.
Article en En | MEDLINE | ID: mdl-38425341
ABSTRACT

Introduction:

Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α).

Methods:

In this study, we evaluated the effects of the HIF-1α inhibitor PX-478 on mesoCAR T cell function through in-silico and in vitro experiments. We conducted comprehensive analyses of HIF-1α expression in cervical cancer patients and examined the impact of PX-478 on T cell proliferation, cytokine production, cytotoxicity, and exhaustion markers.

Results:

Our in-silico analyses revealed high expression of HIF-1α in cervical cancer patients, correlating with poor prognosis. PX-478 effectively reduced HIF-1α levels in T and HeLa cells. While PX-478 exhibited dose-dependent inhibition of antigen-nonspecific T and mesoCAR T cell proliferation, it had minimal impact on antigen-specific mesoCAR T cell proliferation. Notably, PX-478 significantly impaired the cytotoxic function of mesoCAR T cells and induced terminally exhausted T cells.

Discussion:

Our results underscore the significant potential and physiological relevance of the HIF-1α pathway in determining the fate and function of both T and CAR T cells. However, we recognize the imperative for further molecular investigations aimed at unraveling the intricate downstream targets associated with HIF-1α and its influence on antitumor immunity, particularly within the context of hypoxic tumors. These insights serve as a foundation for the careful development of combination therapies tailored to counter immunosuppressive pathways within hypoxic environments and fine-tune CAR T cell performance in the intricate tumor microenvironment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Oncol Año: 2024 Tipo del documento: Article País de afiliación: Irán Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Oncol Año: 2024 Tipo del documento: Article País de afiliación: Irán Pais de publicación: Suiza