Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, CA, USA.
Nat Commun. 2020 Nov 4;11(1):5583. doi: 10.1038/s41467-020-19408-2.
Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. Furthermore, we identify TGFβ as an important mediator of T cell exclusion. TGFβ reduces MHC-I expression in ovarian cancer cells in vitro. TGFβ also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFβ might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.
细胞毒性 T 淋巴细胞与肿瘤细胞的密切接触是免疫治疗有效的必要条件。然而，目前尚不清楚是什么控制了 T 细胞在肿瘤微环境中的空间分布。在这里，我们结合数字病理学和大量卵巢肿瘤队列的转录组分析，开发了一种机器学习方法来对肿瘤免疫表型进行分子分类和特征描述。我们的研究确定了两个重要的特征来描述 T 细胞排斥的肿瘤：1）肿瘤细胞上抗原呈递的丢失，2）TGFβ 和激活的基质的上调。此外，我们发现 TGFβ 是 T 细胞排斥的重要介质。TGFβ 在体外降低卵巢癌细胞中 MHC-I 的表达。TGFβ 还激活成纤维细胞，并诱导细胞外基质的产生，作为潜在的物理屏障来阻碍 T 细胞浸润。我们的研究结果表明，靶向 TGFβ 可能是克服 T 细胞排斥和提高癌症免疫治疗临床获益的一种有前途的策略。
