Zhao Rui, Wan Qianyi, Wang Yong, Wu Yutao, Xiao Shuomeng, Li Qiqi, Shen Xiaoding, Zhuang Wen, Zhou Yong, Xia Lin, Song Yinghan, Chen Yi, Yang Hanshuo, Wu Xiaoting
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
West China College of Stomatology, West China Dental Hospital, Sichuan University, Chengdu, China.
Oncoimmunology. 2020 Dec 30;10(1):1862520. doi: 10.1080/2162402X.2020.1862520.
The efficacy of PD-1/PD-L1 blockades is heterogeneous in different molecular subtypes of gastric cancer (GC). In this study, we analyzed relevant clinical trials to identify the molecular subtypes associated with the efficacy of PD-1/PD-L1 blockades, and public datasets, patient samples, and GC cell lines were used for investigating potential mechanisms. We found that GC with EBV-positive, MSI-H/dMMR, TMB-H or PIK3CA mutant subtype had enhanced efficacy of PD-L1/PD-1 blockades. Also, differentially expressed genes of these molecular subtypes shared the same gene signature and functional annotations related to immunity. Meanwhile, CIBERSORT identified that the overlapping landscapes of tumor-infiltrating immune cells in the four molecular subtypes were mainly M1-like macrophages (M1). The relationships between M1 and clinical characteristics, M1, and gene signatures associated with PD-1/PD-L1 blockades also revealed that M1 was associated with improved prognosis and required for the efficacy of PD-L1/PD-1 blockades in GC. We identified that tumor-infiltrating CD68CD163 macrophages could represent M1 calculated by CIBERSORT in clinical application, and CXCL9, 10, 11/CXCR3 axis was involved in the mechanism of CD68CD163 macrophages in the enhanced efficacy of PD-L1/PD-1 blockades. In conclusion, CD68CD163 macrophages are required for the efficacy of PD-L1/PD-1 blockades and expand the applicable candidates in GC patients without the molecular subtypes.
PD-1/PD-L1阻断剂在胃癌（GC）的不同分子亚型中的疗效存在异质性。在本研究中，我们分析了相关临床试验以确定与PD-1/PD-L1阻断剂疗效相关的分子亚型，并使用公共数据集、患者样本和GC细胞系来研究潜在机制。我们发现，EBV阳性、微卫星高度不稳定/错配修复缺陷（MSI-H/dMMR）、肿瘤突变负荷高（TMB-H）或PIK3CA突变亚型的GC对PD-L1/PD-1阻断剂的疗效增强。此外，这些分子亚型的差异表达基因具有相同的基因特征和与免疫相关的功能注释。同时，CIBERSORT分析表明，四种分子亚型中肿瘤浸润免疫细胞的重叠图谱主要是M1样巨噬细胞（M1）。M1与临床特征、M1以及与PD-1/PD-L1阻断剂相关的基因特征之间的关系还表明，M1与预后改善相关，并且是GC中PD-L1/PD-1阻断剂疗效所必需的。我们确定，肿瘤浸润的CD68⁺CD163⁻巨噬细胞在临床应用中可代表CIBERSORT计算出的M1，并且CXCL9、10、11/CXCR3轴参与了CD68⁺CD163⁻巨噬细胞增强PD-L1/PD-1阻断剂疗效的机制。总之，CD68⁺CD163⁻巨噬细胞是PD-L1/PD-1阻断剂疗效所必需的，并且扩大了无分子亚型的GC患者中的适用候选人群。
