PD-L1 blockade engages tumor-infiltrating lymphocytes to co-express targetable activating and inhibitory receptors
PD-L1 blockade engages tumor-infiltrating lymphocytes to co-express targetable activating and inhibitory receptors
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DOI：
10.1186/s40425-019-0700-3
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发表时间：
2019-08-14
影响因子：
10.9
通讯作者：
Ossendorp, Ferry
中科院分区：
文献类型：
--
作者：
Beyrend, Guillaume;van der Gracht, Esme;Ossendorp, Ferry
背景免疫治疗癌症的临床益处已经得到了很好的证实，尽管仅在少数患者中观察到完全缓解。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治疗提供了一条有吸引力的途径。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，以支持合理设计联合免疫治疗。方法用阻断性PD-L1抗体治疗小鼠皮下MC-38肿瘤。为了建立免疫治疗特异性反应的高维免疫特征，采用38种细胞标记物的CyTOF细胞计数技术分析肿瘤微环境。通过流式细胞术和体内功能实验进一步检验和验证了研究结果。将免疫谱分析扩展到结直肠癌患者的肿瘤微环境。结果PD-L1阻断诱导肿瘤浸润性CD4（+）和CD8(+) t细胞亚群选择性扩增，共同表达激活（ICOS）和抑制（LAG-3, PD-1）分子。通过在体内通过激动剂和拮抗剂抗体将这些分子共同靶向T-AI细胞亚群，我们能够增强PD-L1阻断治疗，这可以通过肿瘤微环境中T-AI细胞数量的增加和肿瘤保护的改善来证明。此外，在结直肠癌患者的肿瘤微环境中也发现了T-AI细胞。结论肿瘤微环境中存在表达激活受体和抑制受体的T细胞亚群。这些T-AI细胞可以通过联合免疫疗法靶向治疗，从而提高生存率。
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 T-AI 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 T-AI cells within the tumor micro-environment and improved tumor protection. Moreover, T-AI 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 T-AI cells can be targeted by combined immunotherapy leading to improved survival.