三阴性乳腺癌免疫疗效关键被发现
三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和抗HER2治疗无效，目前以化疗为主。免疫细胞程序性死亡受体PD-1及其配体PD-L1等免疫检查点的抑制剂可以防止癌细胞逃避被人体免疫细胞杀死，为三阴性乳腺癌的治疗带来了新希望。IMpassion 130研究证实，PD-L1抑制剂阿替利珠单抗（泰圣奇，又称T药）可显著提高晚期三阴性乳腺癌白蛋白紫杉醇一线化疗效果。不过，IMpassion 131研究未能证实阿替利珠单抗可显著提高晚期三阴性乳腺紫杉醇一线化疗效果。
2021年10月14日，美国《细胞》旗下《癌细胞》在线发表北京大学张园园、胡学达、张泽民、中国医学科学院肿瘤医院陈洪岩、莫红楠、牛丽娟、王勇、常青、管秀雯、徐兵河、马飞、刘芝华等学者的研究报告，通过目前最大规模三阴性乳腺癌免疫细胞的单细胞组学分析，发现了阿替利珠单抗＋紫杉醇对三阴性乳腺癌疗效的关键免疫细胞特征。
该研究利用单细胞核糖核酸（RNA）测序和转座酶染色质（ATAC）测序，对11例接受阿替利珠单抗＋紫杉醇化疗和11例接受紫杉醇化疗的晚期三阴性乳腺癌患者治疗前后免疫细胞动态变化进行分析。
结果发现，高水平的治疗前趋化因子配体CXCL13阳性杀伤型（CD8）和辅助型（CD4）T淋巴细胞与巨噬细胞促炎特征显著相关，并且可以预测阿替利珠单抗＋紫杉醇化疗有效。
对于阿替利珠单抗＋紫杉醇化疗有效的患者，联合治疗后淋巴组织诱导细胞、滤泡B淋巴细胞、CXCL13阳性T淋巴细胞、常规1型树突状白细胞一致增加，但是紫杉醇单药化疗后减少。
因此，该研究结果表明，CXCL13阳性T淋巴细胞对于三阴性乳腺癌阿替利珠单抗＋紫杉醇化疗效果至关重要，紫杉醇（或紫杉醇用药前的地塞米松预处理）通过减少某些免疫细胞可能影响阿替利珠单抗治疗三阴性乳腺癌的临床结局。这是国际上迄今为止针对三阴性乳腺癌免疫细胞规模最大的单细胞组学研究，为深入理解三阴性乳腺癌免疫特征以及免疫治疗联合化疗方案的作用机制提供了可靠基础，也为后续相关研究工作提供了极有价值的数据资源。该研究结果为解析肿瘤及其他疾病免疫细胞的动态调控、指导三阴性乳腺癌患者临床分型和精准治疗、开发新的临床检测与治疗手段提供了新的思路。
相关链接
Cancer Cell. 2021 Oct 14. Online ahead of print.
Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer.
Yuanyuan Zhang, Hongyan Chen, Hongnan Mo, Xueda Hu, Ranran Gao, Yahui Zhao, Baolin Liu, Lijuan Niu, Xiaoying Sun, Xiao Yu, Yong Wang, Qing Chang, Tongyang Gong, Xiuwen Guan, Ting Hu, Tianyi Qian, Binghe Xu, Fei Ma, Zemin Zhang, Zhihua Liu
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, International Cancer Institute, Peking University, Beijing, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cancer Hospital of HuanXing ChaoYang District, Beijing, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
HIGHLIGHTS
Dynamic immune cell alterations revealed in TNBC following anti-PD-L1 treatment
CD8-CXCL13 and CD4-CXCL13 T cells predict effective responses to PD-L1 blockade
Proinflammatory macrophages expressing CXCL9 are associated with CXCL13+ T cells
Paclitaxel impairs the expansion of responsive immune cells caused by atezolizumab
In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.
KEYWORDS: triple-negative breast cancer, anti-PD-L1 blockade, single-cell RNA-seq and ATACseq, temporal dynamics, immune cells, atezolizumab in combination with paclitaxel
DOI: 10.1016/j.ccell.2021.09.010