Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model
oleh: Yufei Wang, Jae-Won Cho, Gabriella Kastrunes, Alicia Buck, Cecile Razimbaud, Aedin C. Culhane, Jiusong Sun, David A. Braun, Toni K. Choueiri, Catherine J. Wu, Kristen Jones, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Quan Zhu, Sabina Signoretti, Gordon J. Freeman, Martin Hemberg, Wayne A. Marasco
| Format: | Article |
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| Diterbitkan: | Elsevier 2024-02-01 |
Deskripsi
Summary: 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.