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酪氨酸激酶抑制可激活胃肠道间质瘤中的肿瘤内 γδ T 细胞。

Tyrosine Kinase Inhibition Activates Intratumoral γδ T Cells in Gastrointestinal Stromal Tumor.

机构信息

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

出版信息

Cancer Immunol Res. 2024 Jan 3;12(1):107-119. doi: 10.1158/2326-6066.CIR-23-0061.


DOI:10.1158/2326-6066.CIR-23-0061
PMID:37922405
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10842124/
Abstract

γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were antitumoral, as blockade of either γδ T-cell receptor or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA-seq. Furthermore, tumor γδ T cells correlated with survival in patients with GIST. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.

摘要

γδ T 细胞是一种具有多种功能的罕见但有效的 T 细胞亚群。它们通常存在于肿瘤中,但 γδ T 细胞对酪氨酸激酶抑制的反应尚不清楚。为了解决这个问题,我们研究了一种由致癌性 Kit 信号驱动的胃肠道间质瘤 (GIST) 的基因工程小鼠模型,该模型对 Kit 抑制剂伊马替尼有反应。在基线时,γδ T 细胞具有抗肿瘤作用,因为阻断 γδ T 细胞受体或 IL17A 会增加肿瘤重量并降低抗肿瘤免疫力。然而,伊马替尼治疗进一步刺激了肿瘤内的 γδ T 细胞,这可以通过流式细胞术和单细胞 RNA 测序 (scRNA-seq) 来确定。伊马替尼扩增了具有更高 IL17A 产生和更高免疫检查点和细胞溶解效应分子表达的高度激活的 γδ T 细胞亚群。与小鼠模型一致,γδ T 细胞在新鲜的人类 GIST 标本中产生 IL17A,并且伊马替尼治疗增加了 γδ T 细胞基因特征,这可以通过肿瘤 RNA-seq 来衡量。此外,肿瘤 γδ T 细胞与 GIST 患者的生存相关。我们的研究结果强调了肿瘤细胞癌基因信号与抗肿瘤免疫反应之间的相互作用,并确定 γδ T 细胞是 GIST 免疫治疗的靶点。

相似文献

[1]
Tyrosine Kinase Inhibition Activates Intratumoral γδ T Cells in Gastrointestinal Stromal Tumor.

Cancer Immunol Res. 2024-1-3

[2]
Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor.

Clin Cancer Res. 2017-1-1

[3]
Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity.

Cancer Immunol Res. 2022-10-4

[4]
Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors.

Cancer Res. 2015-5-15

[5]
Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations.

Mol Cancer Ther. 2016-12

[6]
Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor.

Clin Cancer Res. 2014-5-1

[7]
A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance.

Molecules. 2017-12-5

[8]
Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate.

Oncotarget. 2017-1-17

[9]
Macrophages and CD8 T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors.

Cancer Immunol Res. 2018-2-21

[10]
KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors.

Oncotarget. 2016-1-12

引用本文的文献

[1]
Gamma delta T cells in cancer therapy: from tumor recognition to novel treatments.

Front Med (Lausanne). 2024-12-19

[2]
Soft tissue sarcomas at the single-cell and spatial resolution: new markers and targets.

Cancer Gene Ther. 2025-1

本文引用的文献

[1]
γδ T cells are effectors of immunotherapy in cancers with HLA class I defects.

Nature. 2023-1

[2]
Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity.

Cancer Immunol Res. 2022-10-4

[3]
TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets.

Science. 2022-7-15

[4]
A Randomized Phase II Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab in Patients with Advanced Gastrointestinal Stromal Tumors.

Clin Cancer Res. 2022-1-1

[5]
Oncogenic KIT Modulates Type I IFN-Mediated Antitumor Immunity in GIST.

Cancer Immunol Res. 2021-5

[6]
Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer.

Sci Transl Med. 2021-1-20

[7]
γδ T cells in tissue physiology and surveillance.

Nat Rev Immunol. 2021-4

[8]
Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression.

Genome Biol. 2019-12-23

[9]
NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer.

JCI Insight. 2019-12-19

[10]
An innate-like Vδ1 γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer.

Sci Transl Med. 2019-10-9

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