摘要

BACKGROUND:The clinical benefit of immunotherapeutic approaches against cancer has been well established although complete responses are only observed in a minority of patients. Combination immunotherapy offers an attractive avenue to develop more effective cancer therapies by improving the efficacy and duration of the tumor-specific T-cell response. Here, we aimed at deciphering the mechanisms governing the response to PD-1/PD-L1 checkpoint blockade to support the rational design of combination immunotherapy.
METHODS:Mice bearing subcutaneous MC-38 tumors were treated with blocking PD-L1 antibodies. To establish high-dimensional immune signatures of immunotherapy-specific responses, the tumor microenvironment was analyzed by CyTOF mass cytometry using 38 cellular markers. Findings were further examined and validated by flow cytometry and by functional in vivo experiments. Immune profiling was extended to the tumor microenvironment of colorectal cancer patients.
RESULTS:PD-L1 blockade induced selectively the expansion of tumor-infiltrating CD4+ and CD8+ T-cell subsets, co-expressing both activating (ICOS) and inhibitory (LAG-3, PD-1) molecules. By therapeutically co-targeting these molecules on the TAI cell subsets in vivo by agonistic and antagonist antibodies, we were able to enhance PD-L1 blockade therapy as evidenced by an increased number of TAI cells within the tumor micro-environment and improved tumor protection. Moreover, TAI cells were also found in the tumor-microenvironment of colorectal cancer patients.
CONCLUSIONS:This study shows the presence of T cell subsets in the tumor micro-environment expressing both activating and inhibitory receptors. These TAI cells can be targeted by combined immunotherapy leading to improved survival.

译文

背景: 尽管仅在少数患者中观察到完全反应,但针对癌症的免疫治疗方法的临床益处已经得到了很好的证实。联合免疫疗法通过提高肿瘤特异性 T 细胞反应的疗效和持续时间,为开发更有效的癌症疗法提供了一个有吸引力的途径。在这里,我们旨在破译控制 PD-1/PD-L1 检查点阻断反应的机制,以支持联合免疫疗法的合理设计。
方法: 用封闭 MC-38 抗体治疗皮下 PD-L1 肿瘤小鼠。为了建立免疫治疗特异性反应的高维免疫标记,使用 38 个细胞标记物通过 CyTOF 质谱细胞术分析肿瘤微环境。通过流式细胞术和功能性体内实验进一步检查和验证了这些发现。免疫谱扩展到结直肠癌患者的肿瘤微环境。
结果: PD-L1 阻滞选择性地诱导肿瘤浸润 CD4 和 CD8 T 细胞亚群的扩增,同时表达激活 (ICOS) 和抑制 (LAG-3,PD-1) 分子。通过在体内通过激动性抗体和拮抗剂抗体共同治疗靶向这些分子的 TAI 细胞亚群, 我们能够增强 PD-L1 阻断疗法,肿瘤微环境中 TAI 细胞数量的增加和肿瘤保护的改善就是证明。此外,在结直肠癌患者的肿瘤微环境中也发现了 TAI 细胞。
结论: 本研究表明在肿瘤微环境中存在表达激活和抑制受体的 T 细胞亚群。这些 TAI 细胞可以通过联合免疫治疗来靶向,从而提高存活率。

Tumor Infiltrating Lymphocytes

肿瘤 异质细胞 临床研究术语
概述  :  

TILs是指从肿瘤组织中分出出来的浸润淋巴细胞,是一群异质细胞,主要为CD3阳性T细胞,包括CD4阳性及CD8阳性T细胞。目前研究表明肿瘤组织中TILs细胞数量与肿瘤患者治疗及预后存在相关性。同时TILs细胞中具有能够特异识别和杀伤肿瘤的T细胞,通过分离纯化肿瘤组织中的TILs,体外经IL-2扩增培养后回输患者体内,能够治疗和消除转移性肿瘤。因此,其也用于转移性肿瘤治疗,即为TILs细胞疗法,属于过继性免疫细胞治疗的一种。 原理肿瘤浸润淋巴细胞TILs最早由Rosenberg等于1

Tumor   英 /'tju:mə(r)/   美 /'tjʊmɚ/

       n. 肿瘤;肿块;赘生物

       Tumor growth in the body though is a local.  肿瘤虽然是生长在身体的某一局部。

 

Infiltrating   /ɪn'fɪltret/

       v. 渗透;浸润(infiltrate的ing形式)

               adj. 浸润的;浸润性的

       Angiogenesis is correlated to growth, infiltrating and metastasis of renal cell carcinoma (RCC).  肾细胞癌的生长、浸润和转移与血管生成密切相关。

 

Lymphocyte   英 /'lɪmfə(ʊ)saɪt/   美 /'lɪmfə'saɪt/ 

       n. [免疫] 淋巴细胞;淋巴球

       Lymphocyte is a kind of leucocyte of small volume.  淋巴细胞是一种体积较小的白细胞。

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