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
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.
