Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer.
Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer.
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整合数字病理学和转录组分析鉴定卵巢癌中T细胞排斥的分子介质
DOI：
10.1038/s41467-020-19408-2
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发表时间：
2020-11-04
影响因子：
16.6
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Desbois M;Udyavar AR;Ryner L;Kozlowski C;Guan Y;Dürrbaum M;Lu S;Fortin JP;Koeppen H;Ziai J;Chang CW;Keerthivasan S;Plante M;Bourgon R;Bais C;Hegde P;Daemen A;Turley S;Wang Y
细胞毒性T淋巴细胞和肿瘤细胞之间的紧密接近是有效的免疫治疗所必需的。然而，是什么控制了肿瘤微环境中T细胞的空间分布还不清楚。在这里，我们将数字病理学和转录组分析结合在一个大型卵巢肿瘤队列中，并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表征。我们的研究确定了T细胞排除肿瘤的两个重要特征：1）肿瘤细胞上抗原呈递的丧失和2）TGFβ和活化基质的上调。此外，我们确定TGFβ是T细胞排斥的重要介质。TGFβ降低卵巢癌细胞MHC-I表达TGFβ还激活成纤维细胞并诱导细胞外基质产生，作为阻碍T细胞浸润的潜在物理屏障。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效益的一种有前途的策略。从实体瘤中排除T细胞是一种潜在的重要机制，可以调节癌症患者是否对检查点阻断免疫疗法反应良好。在这里，作者确定了ICON 7 III期试验中卵巢癌患者样本的免疫表型和T细胞排斥介质。
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. The exclusion of T cells from solid tumours is a potentially important mechanism that regulates whether or not cancer patients respond well to checkpoint blocking immunotherapies. Here the authors identify immune phenotypes and mediators of T cell exclusion among ovarian cancer patient samples from the ICON7 phase III trial.
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影响因子：
64.5
作者：
Jiménez-Sánchez A;Memon D;Pourpe S;Veeraraghavan H;Li Y;Vargas HA;Gill MB;Park KJ;Zivanovic O;Konner J;Ricca J;Zamarin D;Walther T;Aghajanian C;Wolchok JD;Sala E;Merghoub T;Snyder A;Miller ML
通讯作者：
Miller ML
影响因子：
4.8
作者：
Chang, Chien-Chung;Pirozzi, Giuseppe;Ferrone, Soldano
通讯作者：
Ferrone, Soldano
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
3.7
作者：
Cardenas, Horacio;Vieth, Edyta;Matei, Daniela
通讯作者：
Matei, Daniela
影响因子：
10.9
作者：
Brahmer JR;Govindan R;Anders RA;Antonia SJ;Sagorsky S;Davies MJ;Dubinett SM;Ferris A;Gandhi L;Garon EB;Hellmann MD;Hirsch FR;Malik S;Neal JW;Papadimitrakopoulou VA;Rimm DL;Schwartz LH;Sepesi B;Yeap BY;Rizvi NA;Herbst RS
通讯作者：
Herbst RS