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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	108879
Pages (from-to)	108879
Journal	iScience
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.isci.2024.108879
Publication status	Published - 16 Feb 2024
Externally published	Yes

Keywords

Cancer
Immunology
Transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2024.108879

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Wang, Y., Cho, J. W., Kastrunes, G., Buck, A., Razimbaud, C., Culhane, A. C., Sun, J., Braun, D. A., Choueiri, T. K., Wu, C. J., Jones, K., Nguyen, Q. D., Zhu, Z., Wei, K., Zhu, Q., Signoretti, S., Freeman, G. J., Hemberg, M., & Marasco, W. A. (2024). Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. iScience, 27(2), 108879. Article 108879. https://doi.org/10.1016/j.isci.2024.108879

@article{e8ca09aef7d147598d4f0aa3e6c088e8,

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

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",

author = "Yufei Wang and Cho, {Jae Won} and Gabriella Kastrunes and Alicia Buck and Cecile Razimbaud and Culhane, {Aedin C.} and Jiusong Sun and Braun, {David A.} and Choueiri, {Toni K.} and Wu, {Catherine J.} and Kristen Jones and Nguyen, {Quang De} and Zhu Zhu and Kevin Wei and Quan Zhu and Sabina Signoretti and Freeman, {Gordon J.} and Martin Hemberg and Marasco, {Wayne A.}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = feb,

day = "16",

doi = "10.1016/j.isci.2024.108879",

language = "English",

volume = "27",

pages = "108879",

journal = "iScience",

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Wang, Y, Cho, JW, Kastrunes, G, Buck, A, Razimbaud, C, Culhane, AC, Sun, J, Braun, DA, Choueiri, TK, Wu, CJ, Jones, K, Nguyen, QD, Zhu, Z, Wei, K, Zhu, Q, Signoretti, S, Freeman, GJ, Hemberg, M & Marasco, WA 2024, 'Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model', iScience, vol. 27, no. 2, 108879, pp. 108879. https://doi.org/10.1016/j.isci.2024.108879

TY - JOUR

T1 - Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model

AU - Wang, Yufei

AU - Cho, Jae Won

AU - Kastrunes, Gabriella

AU - Buck, Alicia

AU - Razimbaud, Cecile

AU - Culhane, Aedin C.

AU - Sun, Jiusong

AU - Braun, David A.

AU - Choueiri, Toni K.

AU - Wu, Catherine J.

AU - Jones, Kristen

AU - Nguyen, Quang De

AU - Zhu, Zhu

AU - Wei, Kevin

AU - Zhu, Quan

AU - Signoretti, Sabina

AU - Freeman, Gordon J.

AU - Hemberg, Martin

AU - Marasco, Wayne A.

PY - 2024/2/16

Y1 - 2024/2/16

N2 - 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.

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.

KW - Cancer

KW - Immunology

KW - Transcriptomics

UR - http://www.scopus.com/inward/record.url?scp=85184046452&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2024.108879

DO - 10.1016/j.isci.2024.108879

M3 - Article

AN - SCOPUS:85184046452

SN - 2589-0042

VL - 27

SP - 108879

JO - iScience

JF - iScience

IS - 2

M1 - 108879

ER -

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

Abstract

Keywords

UN SDGs

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