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Tumor Microenvironment Infiltration Patterns, Pathway Network and Genomic Mutations Distinguished by CD8/PD-L1 Levels in Gastric Adenocarcinoma

Background: Although, in gastric cancer (GC), the presence of CD8 T cells and programmed cell death ligand-1(PD-L1) were considered as an inflamed marker for immunotherapy, the objective response rate was only 22% for this kind of patients. Herein, we comprehensively elucidate the gene mutation and expression, and functional enrichment pathways profile basing on CD8 and PD-L1 levels to better understand the immune pattern of inflamed GC and to interpretation the potential clinical treatment strategies to circumvent the obstacle of immunotherapy resistance for patients with different CD8 and PD-L1 levels. 
 
Methods: Histopathologic analysis was used to evaluate PD-L1/ CD8 expression in 186 tumor tissues from GC patients whose survival outcomes were recorded as well. Meanwhile, the gene expression and mutations of 289 GC samples in the Cancer Genome Atlas (TCGA) were computed using R 3.6.1 packages. 
 
Findings: The CD8/PD-L1 subtype were established with Types I (60.3%), II (11.8%), III (0%), and IV (27.9%) in 186 GC samples with survival outcomes related to CD8 T cells level. In 289 GC samples data from TCGA, all four CD8/PD-L1 subtypes had distinguishing molecular subtype with oncogenes and DNA damage repair-related (DDR) genes frequently altered in Type I, while TP53 mutations tend to be enriched in Type II and IV. 
 
Interpretation: We attempted to present a framework for distinguishing and conceptualizing the different signatures among GC with varied PD-L1/CD8 levels rely on histopathological data, gene mutation and expression to provide a new insight into the possibility of overcoming resistance of PD-1/PD-L1 inhibitors. 
 
Funding Statement: The work was supported by in part by Natural Science Foundation of Fujian Province (Grant No. 2017J01259, 2018J01267), Fujian provincial health and family planning research talent training program (Grant No. 2018-ZQN-13,2019-CX-4), Science and Technology Program of Fujian Province, China (Grant No. 2018Y2003, 2019L3018 and 2019YZ016006), Joint Funds for the innovation of science and Technology, Fujian province (Grant No. 2017Y9077，2018Y2003 and 2019YZ016006), Startup Fund for science research, Fujian Medical University (Grant No. 2019QH1196), and the National Clinical Key Specialty Construction Program. 
 
Declaration of Interests: None declared. 
 
Ethics Approval Statement: This study had been informed and approved by the ethics committee of the Fujian Medical University Cancer Hospital. All procedures in the study were conducted conformed to the standards set by the Declaration of Helsinki.