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利用天然T细胞靶向免疫抑制性肿瘤相关巨噬细胞以增强抗肿瘤反应性。

Targeting Immunosuppressive Tumor-Associated Macrophages Using Innate T Cells for Enhanced Antitumor Reactivity.

作者信息

Li Yan-Ruide, Brown James, Yu Yanqi, Lee Derek, Zhou Kuangyi, Dunn Zachary Spencer, Hon Ryan, Wilson Matthew, Kramer Adam, Zhu Yichen, Fang Ying, Yang Lili

机构信息

Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.

出版信息

Cancers (Basel). 2022 Jun 1;14(11):2749. doi: 10.3390/cancers14112749.


DOI:10.3390/cancers14112749
PMID:35681730
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9179365/
Abstract

The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression.

摘要

在过去十年中,基于T细胞和嵌合抗原受体(CAR)工程化T(CAR-T)细胞的抗肿瘤免疫疗法领域取得了重大进展;然而,诸如移植物抗宿主病(GvHD)和肿瘤相关免疫抑制等重大问题已被证明是广泛采用和实施该疗法的重大障碍。基于先天免疫细胞的CAR疗法的最新进展为这种疗法的扩展打开了几扇大门,特别是涉及同种异体细胞来源和实体瘤浸润方面。本研究建立了体外杀伤试验,以检测黏膜相关恒定T细胞(MAIT)、自然杀伤T细胞(iNKT)和γδT细胞靶向肿瘤相关巨噬细胞(TAM)的疗效。本研究还评估了CAR工程化先天T细胞的抗肿瘤能力,评估它们在临床治疗中的潜在应用。本研究中呈现的体外试验证明了所有三种先天T细胞类型均具有相当可观的杀伤TAM的能力,并证实了CAR工程化先天T细胞具有增强的抗肿瘤能力。这些先天T细胞的肿瘤靶向和TAM靶向能力表明它们在抗肿瘤治疗中的潜力,即通过修复肿瘤微环境(TME)免疫抑制来补充细胞毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/4cc533ead74d/cancers-14-02749-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/4cbb71726c2b/cancers-14-02749-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/517f6b1b647b/cancers-14-02749-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/846e12fac4d2/cancers-14-02749-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/46b1a838338b/cancers-14-02749-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/ec7d469cd722/cancers-14-02749-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/4cc533ead74d/cancers-14-02749-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/4cbb71726c2b/cancers-14-02749-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/517f6b1b647b/cancers-14-02749-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/846e12fac4d2/cancers-14-02749-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/46b1a838338b/cancers-14-02749-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/ec7d469cd722/cancers-14-02749-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef52/9179365/4cc533ead74d/cancers-14-02749-g006.jpg

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Biological functions and therapeutic applications of human mucosal-associated invariant T cells.

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[5]
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[6]
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[7]
Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.

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[8]
Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method.

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[9]
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[10]
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本文引用的文献

[1]
An Ex Vivo 3D Tumor Microenvironment-Mimicry Culture to Study TAM Modulation of Cancer Immunotherapy.

Cells. 2022-5-8

[2]
MAOI Antidepressants: Could They Be a Next-Generation ICB Therapy?

Front Immunol. 2022-3-14

[3]
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Stem Cell Res Ther. 2022-3-21

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Cells. 2021-12-10

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Mucosal-associated invariant T (MAIT) cells, a new source of universal immune cells for chimeric antigen receptor (CAR)-cell therapy.

Bull Cancer. 2021-10

[6]
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

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Cell Rep Med. 2021-11-16

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Trends Cancer. 2021-12

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Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021-11

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Nat Commun. 2021-6-10

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