Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify "hot" areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.

译文

:转移性黑素瘤由于其高突变率和新抗原形成而成为最具免疫原性的恶性肿瘤之一。对BRAF抑制剂(BRAFi)的反应可以通过黑色素瘤转移瘤内的肿瘤内免疫激活来确定。为了评估黑色素瘤转移中CD8 T细胞的浸润和分布是否可以预测对BRAFi的临床反应,我们开发了一种方法,将免疫组织化学与CD8 T细胞位置的自动图像分析相结合。 CD8分布模式与基因表达数据相关联,以鉴定和量化肿瘤内的“热”区域。此外,基于转录组学分析,CD8细胞的相对活化及其与肿瘤内其他CD8 T细胞和非CD8细胞的关系表明,活化的CD8 T细胞周围的细胞分布较少。此外,这些CD8 T细胞的相对活化与改善的临床结果和减少的肿瘤细胞增殖有关。这项研究证明了数字病理学在转移中结合免疫细胞空间分布和RNAseq分析来预测转移性黑色素瘤对BRAF抑制的临床反应的潜力。

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