用 DNT 和 LAG3 检查点阻断联合靶向治疗乳腺癌及其机制。

Targeting breast cancer with a combination of DNT and LAG3 checkpoint blockage and its mechanism.

机构信息

Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

出版信息

Immun Inflamm Dis. 2022 Aug;10(8):e626. doi: 10.1002/iid3.626.

DOI:10.1002/iid3.626

PMID:35894707

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9274802/

Abstract

INTRODUCTION

The characteristics of the tumor immune microenvironment (TIME) are closely related to immunotherapy. Breast cancer can benefit from immunotherapy, and its TIME is still unclear.

METHODS

We utilized mass cytometry to explore the immune cell heterogeneity in breast cancer. Double-negative T cells (DNTs) from healthy volunteers (HBs) were enriched in vitro. Flow cytometry was used to detect the cell surface receptors of cancer cells and DNT cells. The correlation between immune checkpoints and the abundance of immune cells or prognosis of breast cancer was analyzed by the TCGA database. The messenger RNA (mRNA) expression of functional genes was performed by quantitative real-time PCR.

RESULTS

We found that the frequencies of Granzyme B (GZMB) CD8 T and GZMB DNT cells in cancer tissues (CA) of breast cancer were lower than those in blood samples of patients (PB), and the frequencies of programmed cell death protein 1 (PD1) CD8 T and PD1 DNT cells in CA were higher than those in PB. DNTs from HBs had a cytotoxic effect on MDA-MB-231. LAG3Ab could upregulate the mRNA expression of interferon gamma and perforin by increasing T-BET transcription to enhance the cytotoxicity of DNT cells in vitro.

CONCLUSION

Our study revealed the suppressive status of TIME in breast cancer and supported DNT cells had the potential to be applied as a novel adoptive cell therapy for TNBC either alone or combined with LAG3Ab.

摘要

简介

肿瘤免疫微环境（TIME）的特征与免疫治疗密切相关。乳腺癌可以从免疫治疗中获益，但其 TIME 仍不清楚。

方法

我们利用液质联用技术（mass cytometry）来探索乳腺癌中的免疫细胞异质性。体外富集健康志愿者（HB）中的双阴性 T 细胞（DNT）。采用流式细胞术检测癌细胞和 DNT 细胞的表面受体。通过 TCGA 数据库分析免疫检查点与免疫细胞丰度或乳腺癌预后的相关性。采用定量实时 PCR 检测功能基因的信使 RNA（mRNA）表达。

结果

我们发现乳腺癌组织（CA）中 Granzzyme B（GZMB）CD8 T 和 GZMB DNT 细胞的频率低于患者血液样本（PB）中的频率，而 CA 中程序性死亡蛋白 1（PD1）CD8 T 和 PD1 DNT 细胞的频率高于 PB。HB 中的 DNT 对 MDA-MB-231 具有细胞毒性作用。LAG3Ab 通过增加 T-BET 转录来上调干扰素 γ和穿孔素的 mRNA 表达，从而增强 DNT 细胞在体外的细胞毒性。