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HLA-DR expression in cytotoxic T lymphocytes
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Orientador(es)
Resumo(s)
T cell-based therapies, involving ex vivo expansion of patients’ T lymphocytes, hold significant promise for chemotherapy resistant cases of breast cancer (BC), although their effectiveness remains challenging. Building on our previous findings that the expression of the antigen presenting molecule, HLA-DR, is crucial on tumor-infiltrating cytotoxic T lymphocytes (CTLs) for a favorable response to neoadjuvant chemotherapy, we further investigated the role of HLA-DR-expressing CTLs in anti-tumor responses and evaluated strategies to amplify these cells. Through in vitro and in vivo experiments, we demonstrated that HLA-DR expression on CTLs is important for effective tumor cell elimination. Notably, blocking HLA-DR or depleting CD4+ T cells impaired CTLs activation, suggesting a critical role for antigen presentation by CTLs to CD4+ T cells through HLA-DR in promoting robust anti-tumor responses. Based on these findings we optimized an ex vivo stimulation protocol that increases the proportion of HLA-DR+CTLs with improved cytotoxicity, prioritizing cell quality over yield. Moreover, we showed that adding anti-PD-1 to the stimulation, further upregulated HLA-DR expression, and intensified CTLs’ cytotoxic ability. This aligns with our in silico analysis suggesting a potential regulatory link between PD-1 and HLA-DR via non-coding RNAs. Overall, our findings open new avenues for advancing T cell-based therapies and improve the outcomes of chemotherapy-resistant-BC.
Descrição
Funding Information: The author(s) declare financial support was received for the research and/or publication of this article. The funding was provided through the Terry Fox Research Grant 2019 from Liga Portuguesa Contra o Cancro, as well as grants from Funda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia (PD/BD/114023/2015 for DPS, SFRH/BD/148422/2019 for RS and 2021.08031.BD for BC), CAPES \u2013 Print (88887.936433/2024-00 for SS), CNPQ (444065/2023-7); iNOVA4Health (UIDB/04462/2020) and LS4FUTURE (LA/P/0087/2020). Funding Information: The author(s) declare financial support was received for the research and/or publication of this article. The funding was provided through the Terry Fox Research Grant 2019 from Liga Portuguesa Contra o Cancro, as well as grants from Funda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia (PD/BD/114023/2015 for DPS, SFRH/BD/148422/2019 for RS and 2021.08031.BD for BC), CAPES \u2013 Print (88887.936433/2024-00 for SS), CNPQ (444065/2023-7); iNOVA4Health (UIDB/04462/2020) and LS4FUTURE (LA/P/0087/2020). Acknowledgments Publisher Copyright: Copyright © 2025 Salvador, Correia, Grosa, Martins, Soares Baal, Saraiva, Cristóvão-Ferreira, Pereira, Rebelo de Almeida, Fior, Jacinto, Mathias, Braga and Cabral.
Palavras-chave
3D co-cultures adoptive T cell therapy breast cancer cytotoxic T lymphocytes cytotoxicity immunomodulation immunotherapy Immunology and Allergy Immunology SDG 3 - Good Health and Well-being