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PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer

PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer

Authors :
Ahmad Reza Panahi Meymandi
Behnia Akbari
Tahereh Soltantoyeh
Zahra Shahosseini
Mina Hosseini
Jamshid Hadjati
Hamid Reza Mirzaei
Source :
Frontiers in Oncology, Vol 14 (2024)
Publication Year :
2024
Publisher :
Frontiers Media S.A., 2024.

Abstract

IntroductionChimeric 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).MethodsIn 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.ResultsOur 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.DiscussionOur 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.

Details

Language :
English
ISSN :
2234943X
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.6420e9ccf5b471fbf5a87c865e61c36
Document Type :
article
Full Text :
https://doi.org/10.3389/fonc.2024.1357801