Immune activity score to assess the prognosis, immunotherapy and chemotherapy response in gastric cancer and experimental validation

Author:

Wu Xuan123,Zhou Fengrui123,Cheng Boran123,Tong Gangling123,Chen Minhua4,He Lirui5,Li Zhu123,Yu Shaokang123,Wang Shubin123,Lin Liping6

Affiliation:

1. Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen, China

2. Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Shenzhen, China

3. Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen, China

4. Community Healthcare Center of Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China

5. Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China

6. Department of Oncology, Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, China

Abstract

Background Gastric cancer (GC) is an extremely heterogeneous malignancy with a complex tumor microenvironment (TME) that contributes to unsatisfactory prognosis. Methods The overall activity score for assessing the immune activity of GC patients was developed based on cancer immune cycle activity index in the Tracking Tumor Immunophenotype (TIP). Genes potentially affected by the overall activity score were screened using weighted gene co-expression network analysis (WGCNA). Based on the expression profile data of GC in The Cancer Genome Atlas (TCGA) database, COX analysis was applied to create an immune activity score (IAS). Differences in TME activity in the IAS groups were analyzed. We also evaluated the value of IAS in estimating immunotherapy and chemotherapy response based on immunotherapy cohort. Gene expression in IAS model and cell viability were determined by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and Cell Counting Kit-8 (CCK-8) assay, respectively. Results WGCAN analysis screened 629 overall activity score-related genes, which were mainly associated with T cell response and B cell response. COX analysis identified AKAP5, CTLA4, LRRC8C, AOAH-IT1, NPC2, RGS1 and SLC2A3 as critical genes affecting the prognosis of GC, based on which the IAS was developed. Further RT-qPCR analysis data showed that the expression of AKAP5 and CTLA4 was downregulated, while that of LRRC8C, AOAH-IT1, NPC2, RGS1 and SLC2A3 was significantly elevated in GC cell lines. Inhibition of AKAP5 increased cell viability but siAOAH-IT1 promoted viability of GC cells. IAS demonstrated excellent robustness in predicting immunotherapy outcome and GC prognosis, with low-IAS patients having better prognosis and immunotherapy. In addition, resistance to Erlotinib, Rapamycin, MG-132, Cyclopamine, AZ628, and Sorafenib was reduced in patients with low IAS. Conclusion IAS was a reliable prognostic indicator. For GC patients, IAS showed excellent robustness in predicting GC prognosis, immune activity status, immunotherapy response, and chemotherapeutic drug resistance. Our study provided novel insights into the prognostic assessment in GC.

Funder

Basic Research Program of Shenzhen Innovation Council

Shenzhen Science and Technology Innovation Commission Project

Shenzhen Sanming Project

Shenzhen Science, Technology Innovation Commission Project

Guangzhou Science and Technology Project of Traditional Chinese medicine and Integrated Traditional and Western Medicine

Publisher

PeerJ

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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