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揭示CD4+嵌合抗原受体T细胞在癌症免疫治疗中的作用。

Uncovering the Role of CD4+ CAR T Cells in Cancer Immunotherapy.

作者信息

Alizadeh Darya, Wang Dongrui, Brown Christine E

机构信息

Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope, Beckman Research Institute and Medical Center, Duarte, California.

Bone Marrow Transplantation Center, the First Affiliated Hospital of Zhejiang University School of Medicine, and Liangzhu Laboratory, Hangzhou, Zhejiang, P.R. China.

出版信息

Cancer Res. 2023 Sep 1;83(17):2813-2815. doi: 10.1158/0008-5472.CAN-23-1948.


DOI:10.1158/0008-5472.CAN-23-1948
PMID:37404063
Abstract

Chimeric antigen receptor (CAR) T-cell therapy has transformed clinical care against blood malignancies and is seeing encouraging progress against solid tumors. While scientific advancement has been rapid, our mechanistic understanding of intrinsic features of CAR-engineered T cells is still evolving. CAR products typically consist of CD4+ and CD8+ T-cell subsets at variable ratios, yet a clear understanding of how each subset contributes together and independently to therapeutic response is lacking. CD8+ CAR T cells are well characterized for their perforin-dependent killing effects; however, the role of CD4+ CAR T cells as "helpers" versus "killers" has been variable across models and warrants more in-depth investigation. A recent study by Boulch and colleagues published in Nature Cancer demonstrates that CD4+ CAR T cells, alone, can exert potent antitumor activity through a mechanism involving IFNγ. CD4+ CAR T-cell production of IFNγ creates a cytokine field that can act at a distance to kill both antigen-positive and -negative tumor cells that are sensitive to the proapoptotic effects of IFNγ. These new findings reveal important insights for the antitumor effects mediated by CD4+ CAR T cells, which could have significant clinical implications.

摘要

嵌合抗原受体(CAR)T细胞疗法已经改变了针对血液系统恶性肿瘤的临床治疗方式,并且在针对实体瘤的治疗方面也取得了令人鼓舞的进展。尽管科学进步迅速,但我们对CAR工程化T细胞内在特征的机制理解仍在不断发展。CAR产品通常由比例可变的CD4+和CD8+ T细胞亚群组成,但目前尚缺乏对每个亚群如何共同及独立地影响治疗反应的清晰认识。CD8+ CAR T细胞因其依赖穿孔素的杀伤作用而得到了充分表征;然而,在不同模型中,CD4+ CAR T细胞作为“辅助细胞”与“杀伤细胞”的作用存在差异,需要更深入的研究。Boulch及其同事最近发表在《自然·癌症》上的一项研究表明,单独的CD4+ CAR T细胞可通过一种涉及IFNγ的机制发挥强大的抗肿瘤活性。CD4+ CAR T细胞产生的IFNγ会形成一个细胞因子场,该细胞因子场可在一定距离外发挥作用,杀死对IFNγ的促凋亡作用敏感的抗原阳性和阴性肿瘤细胞。这些新发现揭示了CD4+ CAR T细胞介导的抗肿瘤作用的重要见解,可能具有重大的临床意义。

相似文献

[1]
Uncovering the Role of CD4+ CAR T Cells in Cancer Immunotherapy.

Cancer Res. 2023-9-1

[2]
Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity.

JCI Insight. 2018-5-17

[3]
Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4 CAR T-cell antitumor activity.

Nat Cancer. 2023-7

[4]
Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models.

Cancers (Basel). 2021-8-26

[5]
Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma.

J Immunother Cancer. 2021-12

[6]
β-.

J Immunother Cancer. 2020-4

[7]
Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo.

Leukemia. 2016-2

[8]
Most Do, but Some Do Not: CD4⁺CD25 T Cells, but Not CD4⁺CD25⁺ Treg Cells, Are Cytolytic When Redirected by a Chimeric Antigen Receptor (CAR).

Cancers (Basel). 2017-8-29

[9]
A major role for CD4 T cells in driving cytokine release syndrome during CAR T cell therapy.

Cell Rep Med. 2023-9-19

[10]
New insights into CAR T cell-mediated killing of tumor cells.

Front Immunol. 2022

引用本文的文献

[1]
A multi-scale semi-mechanistic CK/PD model for CAR T-cell therapy.

Front Syst Biol. 2024-8-29

[2]
CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses.

Sci Adv. 2025-4-11

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