Mutual exclusivity and co-occurrence patterns of immune checkpoints indicate NKG2A relates to anti-PD-1 resistance in gastric cancer

作者：Guanjun Li, Xiaohan Liu, Chunhui Gu, Guichuang Ma, Shao-wei Li, Zhenfeng Ma, Yanqiu Xiong, Jiang Yu, Qiong Huang, Jianhua Wu, Zhenhua Wu, Wangjun Liao, Qijing Wu, Min Shi · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05503-1 · 被引用次数：17 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Chemokine receptors and signaling

An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, ...