PMID- 38327771
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240211
IS  - 2589-0042 (Electronic)
IS  - 2589-0042 (Linking)
VI  - 27
IP  - 2
DP  - 2024 Feb 16
TI  - Immune-restoring CAR-T cells display antitumor activity and reverse 
      immunosuppressive TME in a humanized ccRCC mouse model.
PG  - 108879
LID - 10.1016/j.isci.2024.108879 [doi]
LID - 108879
AB  - 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.
CI  - (c) 2024.
FAU - Wang, Yufei
AU  - Wang Y
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02215, USA.
FAU - Cho, Jae-Won
AU  - Cho JW
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, 
      Boston, MA 02115, USA.
FAU - Kastrunes, Gabriella
AU  - Kastrunes G
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
FAU - Buck, Alicia
AU  - Buck A
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
FAU - Razimbaud, Cecile
AU  - Razimbaud C
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
FAU - Culhane, Aedin C
AU  - Culhane AC
AD  - School of Medicine, University of Limerick, V94 T9PX Limerick, Ireland.
FAU - Sun, Jiusong
AU  - Sun J
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
FAU - Braun, David A
AU  - Braun DA
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 
      USA.
AD  - Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of 
      Medicine, New Haven, CT 06525, USA.
FAU - Choueiri, Toni K
AU  - Choueiri TK
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 
      USA.
FAU - Wu, Catherine J
AU  - Wu CJ
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 
      USA.
FAU - Jones, Kristen
AU  - Jones K
AD  - Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, 
      Dana-Farber Cancer Institute, Boston, MA 02215, USA.
FAU - Nguyen, Quang-De
AU  - Nguyen QD
AD  - Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, 
      Dana-Farber Cancer Institute, Boston, MA 02215, USA.
FAU - Zhu, Zhu
AU  - Zhu Z
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Division of Rheumatology, Inflammation and Immunity, Brigham and Women's 
      Hospital, Boston, MA 02115, USA.
FAU - Wei, Kevin
AU  - Wei K
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Division of Rheumatology, Inflammation and Immunity, Brigham and Women's 
      Hospital, Boston, MA 02115, USA.
FAU - Zhu, Quan
AU  - Zhu Q
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02215, USA.
FAU - Signoretti, Sabina
AU  - Signoretti S
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 
      02215, USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Freeman, Gordon J
AU  - Freeman GJ
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 
      USA.
FAU - Hemberg, Martin
AU  - Hemberg M
AD  - Harvard Medical School, Boston, MA 02215, USA.
AD  - Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, 
      Boston, MA 02115, USA.
FAU - Marasco, Wayne A
AU  - Marasco WA
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02215, USA.
LA  - eng
GR  - P30 CA006516/CA/NCI NIH HHS/United States
GR  - P50 CA101942/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20240115
PL  - United States
TA  - iScience
JT  - iScience
JID - 101724038
PMC - PMC10847687
OTO - NOTNLM
OT  - Cancer
OT  - Immunology
OT  - Transcriptomics
COIS- W.A.M. has patents in the PD-1/PDL1 field. G.J.F. has patents/pending royalties 
      on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, 
      Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, Eli Lilly, and 
      Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, 
      Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Trillium, IOME, GV20, 
      Invaria, and Geode. G.J.F. has equity in NextPoint, Triursus, Xios, iTeos, IgM, 
      GV20, Invaria, and Geode. M.H. is a co-founder of Neomer Diagnostics where he is 
      also on the advisory board. K.W. received a sponsored-research agreement from 
      Gilead Sciences. K.W. served as a consultant for Gilead Sciences and Horizon 
      Therapeutics. D.A.B. reports nonfinancial support from Bristol Myers Squibb, 
      honoraria from LM Education/Exchange Services, advisory board fees from Exelixis 
      and AVEO, personal fees from Charles River Associates, Schlesinger Associates, 
      Imprint Science, Insight Strategy, Trinity Group, Cancer Expert Now, Adnovate 
      Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, 
      PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, 
      Targeted Oncology, and AbbVie, and research support from Exelixis and 
      AstraZeneca, outside of the submitted work. C.J.W. holds equity in BioNTech, 
      Inc., and receives research funding from Pharmacyclics. S.S. reports receiving 
      commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis, and 
      Novartis; is a consultant/advisory board member for Merck, AstraZeneca, 
      Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; receives royalties 
      from Biogenex; and mentored several non-US citizens on research projects with 
      potential funding (in part) from non-US sources/Foreign Components. T.K.C. 
      reports institutional and personal, paid and unpaid support for research, 
      advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, 
      Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, 
      Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, 
      Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, 
      Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, and others), 
      outside the submitted work. T.K.C. has institutional patents filed on molecular 
      alterations and immunotherapy response/toxicity, and ctDNA. T.K.C. has equity in 
      Tempest, Pionyr, Osel, and Precede Bio. T.K.C. has served on committees for NCCN, 
      GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. T.K.C. has medical 
      writing and editorial assistance support may have been funded by Communications 
      companies in part. T.K.C. has mentored several non-US citizens on research 
      projects with potential funding (in part) from non-US sources/Foreign Components. 
      The institution (Dana-Farber Cancer Institute) may have received additional 
      independent funding of drug companies or/and royalties potentially involved in 
      research around the subject matter.
EDAT- 2024/02/08 06:42
MHDA- 2024/02/08 06:43
PMCR- 2024/01/15
CRDT- 2024/02/08 04:10
PHST- 2023/10/12 00:00 [received]
PHST- 2023/12/01 00:00 [revised]
PHST- 2024/01/08 00:00 [accepted]
PHST- 2024/02/08 06:43 [medline]
PHST- 2024/02/08 06:42 [pubmed]
PHST- 2024/02/08 04:10 [entrez]
PHST- 2024/01/15 00:00 [pmc-release]
AID - S2589-0042(24)00100-7 [pii]
AID - 108879 [pii]
AID - 10.1016/j.isci.2024.108879 [doi]
PST - epublish
SO  - iScience. 2024 Jan 15;27(2):108879. doi: 10.1016/j.isci.2024.108879. eCollection 
      2024 Feb 16.