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

iScience (Feb 2024)

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

Affiliations

Yufei Wang: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA
Jae-Won Cho: Harvard Medical School, Boston, MA 02215, USA; Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Boston, MA 02115, USA
Gabriella Kastrunes: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Alicia Buck: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Cecile Razimbaud: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Aedin C. Culhane: School of Medicine, University of Limerick, V94 T9PX Limerick, Ireland
Jiusong Sun: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
David A. Braun: Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06525, USA
Toni K. Choueiri: Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Catherine J. Wu: Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Kristen Jones: Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Quang-De Nguyen: Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Zhu Zhu: Harvard Medical School, Boston, MA 02215, USA; Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston, MA 02115, USA
Kevin Wei: Harvard Medical School, Boston, MA 02215, USA; Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston, MA 02115, USA
Quan Zhu: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA
Sabina Signoretti: Harvard Medical School, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Gordon J. Freeman: Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Martin Hemberg: Harvard Medical School, Boston, MA 02215, USA; Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Boston, MA 02115, USA
Wayne A. Marasco: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Corresponding author

Journal volume & issue: Vol. 27, no. 2
p. 108879

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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