Transcriptomic analysis of MSI-H/dMMR GI tumors to identify determinants of response to PD-1 inhibitor therapy

IF:12.531( /strong>2021)< /span>

yesMSI-H/dMMR< /span>GITumor transcriptomic analysis to determine /strong>PD-1Determinants of response to inhibitor therapy

[Objective]Transcriptomic analysis of patients with MSI-H/dMMR GI tumors to determine Predictors of response to PD-1 inhibitors.

[Experimental Design] Analysis of 36 PD-1 inhibitor-treated patients with MSI-H/dMMR GI tumors, including gastric, colorectal, bile duct, small bowel, and pancreatic cancers. This experiment performed transcriptomic analysis of patients with GI tumors using RNA-sequencing data, including consensus molecular subtypes (CMS) of colorectal cancer.

[results]< span>Gene set enrichment analysis (GSEA) revealed epithelial-mesenchymal transition, angiogenesis, hypoxia, mTORC1, tumor necrosis factor alpha (TNF-α), KRAS, Wnt in non-responders to PD-1 inhibitor therapy /β-catenin, TGF-β and various metabolism-related signaling pathways were all up-regulated. Meanwhile, the interferon gamma (IFN-γ) pathway was enriched in responders to PD-1 inhibitor therapy. Based on GSEA leading-edge analysis, VEGF-A was significantly associated with enriched pathways in non-responders. Patients with high VEGF-A expression had PFS [median 4.8 months vs not reached (NR), P=0.032] and OS (median 11.1 months vs NR, P=0.045) compared with patients with low VEGF-A expression ) were significantly shortened. Among the 13 CRC patients assessed for CMS classification, the objective response rates for CMS1, CMS2, CMS3, and CMS4 were 100%, 0%, 0%, and 16.7%, respectively. Patients with stage CMS1 had significantly longer PFS than patients with stage CMS2, CMS3, or CMS4 (NR vs 4.8 months, P=0.017).

[Conclusion]< span>In patients with MSI-H/dMMR GI tumors, several transcriptomic signatures, including CMS classification and associated genes, were associated with responses to PD-1 inhibitors. These findings could aid in the development of predictive biomarkers or immune combination therapies.

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Expert Comments

MSI-H/dMMR tumors are heterogeneous , there is a decisive molecular mechanism behind it. In this study, 36 MSI-H/dMMR patients treated with PD-1 mAb were analyzed by transcriptomic method, and it was found that IFN-γ pathway, low expression of VEGF-A and CMS1 intestinal Cancer immunotherapy has better efficacy. On the one hand, these results provide a reference for further optimization of the beneficiary population in MSI-H/dMMR tumors. At the same time, this study also found that the poor response population has specific enrichment pathways, such as angiogenesis, or These results provide a very good solution for reversing drug resistance.

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Review experts

Professor Qu Xiujuan

Chief Physician Doctoral Supervisor

Director of Medical Oncology, The First Affiliated Hospital of China Medical University


Director of CSCO

Member of the Standing Committee of CSCO Gastric Cancer Expert Committee

Member of CSCO Immunotherapy Special Committee

Member of CSCO Smart Medical Expert Committee

CSCO Anti-tumor Drug Safety Management Committee member

Vice-chairman of the Youth Committee of CACA Cancer Targeted Therapy Professional Committee

Oncology Branch of Chinese Medical Association Member of the Gastric Cancer Group

Member of the Colorectal Cancer Professional Committee of the Chinese Medical Doctor Association

Chairman of the Oncology Branch of the Liaoning Provincial Society of Immunology

Chairman-designate of the Biomarkers Professional Committee of Liaoning Anti-Cancer Association

Presided over 1 major scientific and technological project, the national 5 Natural Science Awards, 2 Provincial Science and Technology Progress First Prizes, Published more than 100 SCI papers as the first or corresponding author in JCO and other journals.



1. Fucà G, Cohen R, Lonardi S, et al. J Immunother Cancer. 2022 Feb;10(2): e004001.

2. Chida K, Kawazoe A, Suzuki T, et al. Clin Cancer Res. 2022 Mar 7: clincanres. 0041. 2022.

3. Zhuo N, Liu C, Zhang Q, et al. JAMA Netw Open. 2022 Mar 1;5(3): e224637.

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