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Abstract
Background Immune interactions in the tumor microenvironment (TME) are a major factor in deciding the fate of immunotherapy. Heterogeneity and molecular subtypes, especially in solid tumors like gastric cancer (GC), involve substantial modification in TME. Hence understanding the immune cell populations infiltrating the TME of different molecular subtypes will help to develop more effective and targeted therapies
Methods CBioPortal 1,2 was used to extract and analyze The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma Pan-Cancer Atlas Data (STAD). Immune Metagene signatures from previous publications3 were used to analyze the immune infiltration landscape in different GC molecular subtypes- chromosomal instability (CIN)(n=223), microsatellite instable (MSI)(n=73), genomically stable (GS)(n=50), Epstein–Barr virus (EBV) associated (n=30). GraphPad Prism9 and MS Excel were used to analyze the data and generate the figures.
Results We analyzed the infiltration landscape of Natural Killer (NK) cells, T cells ( CD4+, CD8+, Th1, Th2, Th17), immune suppressive Myeloid-derived suppressor cells (MDSC), and Regulatory T cells (Tregs) in GC molecular subtypes. The results showed that CD8+ cytotoxic T cells and CD4+ helper T cells were highly downregulated in the GS subtype in comparison to other molecular subtypes (figure 1). Cytokine secreting T helper cell subsets, Th1, Th2, and Th17 demonstrate a dissimilar infiltration pattern among subtypes (figure 2). Th1 cells were highly expressed in the EBV subtype as compared to Th1 infiltration in the other subtypes (figure 3). GS and EBV both depict higher infiltration of Th2 cells and lower infiltration of Th17 cells in comparison to CIN and MSI subtypes (figure 2). GS subtype along with EBV has a superior infiltration of immune suppressive MDSC and Tregs (figure 3). Both cytotoxic NK56dim and cytokine secreting immune modulating NK56bright cells were the lowest infiltrating the GS molecular subtype (figure 4). Intriguingly, NK56bright infiltration markers don’t differ significantly between subtypes. It was worth observing that in general, there is more infiltration of NK56dim over NK56bright cells in GC patients (figure 4).
Conclusions TME of the GS molecular subtype of GC contains less cytotoxic cells (NK56Dim and CD8+ T) and higher infiltration of immune suppressive cells (Tregs and MDSCs).
Acknowledgements This research was supported by UNAM DGAPA grant to Dr. Sanyog Dwivedi (Feb 2022- Jan 2023).
References
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Immune cell infiltration landscape of T cells ( CD4+, CD8+) cells by GC molecular subtypes. Statistical significance was confirmed using one-way ANOVA, P-Value,**** <0.0001
Immune cell infiltration landscape of Th1, Th2, and Th17 cells by GC molecular subtypes. Statistical significance was confirmed using one-way ANOVA, P-Value, **-0.0045, ***-0.0002,**** <0.0001
Immune cell infiltration landscape of MDSC and Tregs by GC molecular subtypes. Statistical significance was confirmed using one-way ANOVA, P-Value, **-0.0045, ***-0.0002,**** <0.0001
Immune cell infiltration landscape of NK56bright and NK56dim cells by GC molecular subtypes. Statistical significance was confirmed using one-way ANOVA, P-Value, **** <0.0001