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Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model

iScience, ISSN: 2589-0042, Vol: 27, Issue: 2, Page: 108879
2024
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Article Description

One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34 + hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8 + T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

Bibliographic Details

Wang, Yufei; Cho, Jae-Won; Kastrunes, Gabriella; Buck, Alicia; Razimbaud, Cecile; Culhane, Aedin C; Sun, Jiusong; Braun, David A; Choueiri, Toni K; Wu, Catherine J; Jones, Kristen; Nguyen, Quang-De; Zhu, Zhu; Wei, Kevin; Zhu, Quan; Signoretti, Sabina; Freeman, Gordon J; Hemberg, Martin; Marasco, Wayne A

Elsevier BV

Multidisciplinary

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