| Autor: |
Patel, Ruchi P., Ghilardi, Guido, Zhang, Yunlin, Chiang, Yi-Hao, Xie, Wei, Guruprasad, Puneeth, Kim, Ki Hyun, Chun, Inkook, Angelos, Mathew G., Pajarillo, Raymone, Hong, Seok Jae, Lee, Yong Gu, Shestova, Olga, Shaw, Carolyn, Cohen, Ivan, Gupta, Aasha, Vu, Trang, Qian, Dean, Yang, Steven, Nimmagadda, Aditya |
| Předmět: |
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| Zdroj: |
Science Immunology; Jul2024, Vol. 9 Issue 97, p1-16, 16p |
| Abstrakt: |
Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies. Editor's summary: The currently available chimeric antigen receptor (CAR) T cell therapies have had limited efficacy for a wide range of solid cancers and hematological malignancies, due in part to CAR T cell dysfunction. The scavenger receptor CD5 associates with the T cell receptor (TCR) and inhibits T cell function. Patel et al. show that genetic deletion of CD5 in CAR and TCR T cells enhances expansion, persistence, and cytotoxicity and is effective in preclinical solid tumor and hematological malignancy models. These results suggest that CD5 may be a critical negative regulator of CAR T cells that can be therapeutically targeted. —Christiana Fogg [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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