以色列魏茨曼科学研究所的Yardena Samuels与美国国立癌症研究所的Eytan Ruppin等研究人员合作发现，UVB诱导的肿瘤异质性能够削减黑色素瘤的免疫响应。该研究于2019年9月12日在线发表于《细胞》杂志。
研究人员在一个新的小鼠可控黑色素瘤模型中研究了这个问题，这使得研究人员能够探索肿瘤内异质性（ITH）对肿瘤侵袭性和免疫力的影响，而不受肿瘤突变负荷的干扰。UVB来源突变的引发能够产生具有抗肿瘤活性降低的高度侵袭性肿瘤。然而，具有降低ITH的单细胞来源的肿瘤被迅速清除。这一排斥反应伴随着T细胞反应性的增加和抑制性微环境的降低。利用系统发育分析和单细胞克隆混合实验，研究人员剖析了ITH的两个特征：形成肿瘤的克隆数量及其克隆多样性。研究人员对黑素瘤患者肿瘤数据的分析概括了总体存活率和对免疫检查点治疗反应方面的结果。
这些研究结果突出了克隆突变在强大的免疫监视中的重要性，以及量化患者ITH以确定对检查点阻滞反应的必要性。
研究人员表示，虽然克隆性新抗原负担与免疫疗法的反应提升有关，但其功能基础仍不清楚。
附：英文原文
Title: UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma
Author: Yochai Wolf, Osnat Bartok, Sushant Patkar, Gitit Bar Eli, Sapir Cohen, Kevin Litchfield, Ronen Levy, Alejandro Jiménez-Sánchez, Sophie Trabish, Joo Sang Lee, Hiren Karathia, Eilon Barnea, Chi-Ping Day, Einat Cinnamon, Ilan Stein, Adam Solomon, Lital Bitton, Eva Pérez-Guijarro, Tania Dubovik, Shai S. Shen-Orr, Martin L. Miller, Glenn Merlino, Yishai Levin, Eli Pikarsky, Lea Eisenbach, Arie Admon, Charles Swanton, Eytan Ruppin, Yardena Samuels
Issue&Volume: 12 September 2019
Summary:
Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.
DOI: 10.1016/j.cell.2019.08.032
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30951-1