Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer.
Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer.
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发表时间：
2021
影响因子：
5.3
通讯作者：
M. Oshi;T. Kawaguchi;Li Yan;Xuan Peng;Qianya Qi;W. Tian;Amy K Schulze;Kerry-Ann McDonald;Sumana Narayanan;Jessica S. Young;Song Liu;L. Morris;T. Chan;P. Kalinski;R. Matsuyama;E. Otsuji;I. Endo;K. Takabe
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作者：
M. Oshi;T. Kawaguchi;Li Yan;Xuan Peng;Qianya Qi;W. Tian;Amy K Schulze;Kerry-Ann McDonald;Sumana Narayanan;Jessica S. Young;Song Liu;L. Morris;T. Chan;P. Kalinski;R. Matsuyama;E. Otsuji;I. Endo;K. Takabe
肿瘤免疫微环境（TIME）功能方面的评价，如最近引入的细胞溶解活性评分（CYT）指数，一直是癌症研究的焦点;然而，乳腺癌中免疫细胞杀伤活性的临床相关性从未在大型患者队列中进行过分析。我们假设CYT反映了TIME的免疫活性，可以预测患者的生存。共有7533例乳腺癌患者作为发现和验证队列进行了分析。我们发现高CYT与晚期组织学分级和三阴性乳腺癌（TNBC）相关。肿瘤中的高CYT与TNBC的更好生存率显著相关，但出乎意料的是，在其他乳腺癌亚型中并非如此。高CYT TNBC包括有利的免疫相关以及不利的（抑制性）炎症相关基因集，并且特征在于T细胞和B细胞的高浸润。高CYT TNBC与高同源重组缺陷和低体细胞拷贝数改变评分以及较少的突变等位基因肿瘤异质性相关，但与肿瘤突变负荷（TMB）无关。虽然CYT与新辅助化疗后的病理完全缓解无关，但与多种免疫检查点分子的高表达显著相关。总之，TNBC的CYT与增强的抗癌免疫力、更少的肿瘤内异质性和更好的生存率相关。
Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.