Tang, Che et al. utilized semi-supervised learning to stratify potential ICI responders among patients with microsatellite-stable gastric cancers (MSS GCs). The abundance of T-bet+ CD8+ T cells correlated with response to ICI treatment (AUC of 0.8), and there was a strong association with PIK3CA mutation and 9p24 amplification as well. IFNγ signaling pathway and CXCL9/10/11–CXCR3 chemotaxis pair-mediated spatial organizations of T-bet+ T cells and PD-L1+ tumor cell niches determined the sensitivity to ICI. Adoptive transfer of T-bet+ CD8+ T cells reinvigorated tumor immune microenvironments and sensitized immune-ignorant tumors to ICIs in humanized mouse models.
Contributed by Shishir Pant
ABSTRACT: More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8_+_T cell infiltration in their tumor compartments. T-bet+ CD8_+_T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8_+_T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.
Author Info: (1) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Bioth
Author Info: (1) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (2) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (3) Department of Immunology, College of Basic Medical Sciences, China Medical University, No. 77, Puhe Road, Shenyang, Liaoning, China. (4) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (5) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (6) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (7) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (8) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (9) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (10) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (11) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (12) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. xjqu@cmu.edu.cn. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. xjqu@cmu.edu.cn. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. xjqu@cmu.edu.cn. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. xjqu@cmu.edu.cn. (13) Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, No.155, Nanjing Street, Shenyang, Liaoning, China. znwang@cmu.edu.cn. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, China Medical University, Shenyang, Liaoning, China. znwang@cmu.edu.cn. Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China. znwang@cmu.edu.cn. (14) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. ypliu@cmu.edu.cn. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. ypliu@cmu.edu.cn. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. ypliu@cmu.edu.cn. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. ypliu@cmu.edu.cn.
