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

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

doi:10.1016/j.isci.2024.108879

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

iScience. 2024 Jan 15;27(2):108879. doi: 10.1016/j.isci.2024.108879. eCollection 2024 Feb 16.

Authors

Yufei Wang^{1

2}, Jae-Won Cho^{2

3}, Gabriella Kastrunes¹, Alicia Buck¹, Cecile Razimbaud¹, Aedin C Culhane⁴, Jiusong Sun¹, David A Braun^{2

5

6}, Toni K Choueiri^{2

5}, Catherine J Wu^{2

5}, Kristen Jones⁷, Quang-De Nguyen⁷, Zhu Zhu^{2

8}, Kevin Wei^{2

8}, Quan Zhu^{1

2}, Sabina Signoretti^{2

9

10}, Gordon J Freeman^{2

5}, Martin Hemberg^{2

3}, Wayne A Marasco^{1

2}

Affiliations

¹ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Harvard Medical School, Boston, MA 02215, USA.
³ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ School of Medicine, University of Limerick, V94 T9PX Limerick, Ireland.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06525, USA.
⁷ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁹ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.

Abstract

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.

Keywords: Cancer; Immunology; Transcriptomics.

Abstract

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