Abstract
BackgroundProgrammed cell death protein 1(PD-1) blocking antibodies have been used to enhance immunity in solid tumors and achieve durable clinical responses with an acceptable safety profile in multiple types of cancer. However, only a subset of patients could benefit from PD-1 blockade therapy. Prognostic information including PD-1 ligand (PD-L1) expression, IFN-γ expression signature, tumor mutational burden, and microsatellite instability (MSI) have been evaluated for patients who are selected to receive immune checkpoint therapeutic treatment. Yet the relationship of those biomarkers in determining immune checkpoint therapy is largely unknown.MethodsImmune-profiles of MSI subtype colon cancer were identified from integrating published MSI associated gene expression data. The enriched pathways and transcription factors were analyzed by GSEA assay. The infiltrations of immune cell types into MSI subtype colon cancer tissues were determined by CIBESORT assay.ResultsIn the MSI subtype colon cancer patients, PD-L1, IFN-γ and IFN-γ associated genes are highly expressed. And all those genes are favorable effects in colon cancer progress. In addition, we find that Wnt-β-catenin and TGFβ signaling pathways which are two important factors inhibiting PD-1 checkpoint blockade therapy are negatively related with MSI status. We also identify that the immune-profiles in MSI subtype colon cancer are contributed by M1 macrophage infiltration in the tumor environment.ConclusionsOur results provide the detailed underlying mechanisms of MSI subtype cancer patients are sensitive to PD-1 checkpoint blockade.
Highlights
Programmed cell death protein 1(PD-1) blocking antibodies have been used to enhance immunity in solid tumors and achieve durable clinical responses with an acceptable safety profile in multiple types of cancer
We found that TGFβ signaling associated genes TGFBR2 and TGFBI was highly expressed in microsatellite stability (MSS) subtype of colon cancer (Fig. 3b), suggesting the potential inhibition of PD-1 ligand (PD-L1) and IFN-γ are activated in CMS1 colon cancer subtype patients Previously, multiple colon subtypes had been identified with different methods based on the DNA methylation, DNA somatic copy number alterations (SCNA) or gene expression profiling [29,30,31]
microsatellite instability (MSI) subtype colon cancer patients are with high M1 macrophage infiltration Recent studies suggested that the immune cell infiltration could increase PD-L1 expression in cancer cells and enhance the response to anti-PD-1 therapies [13]
Summary
Programmed cell death protein 1(PD-1) blocking antibodies have been used to enhance immunity in solid tumors and achieve durable clinical responses with an acceptable safety profile in multiple types of cancer. Prognostic information including PD1 ligand (PD-L1) expression, IFN-γ expression signature, tumor mutational burden, and microsatellite instability (MSI) have been evaluated for patients who are selected to receive immune checkpoint therapeutic treatment. Germ line mutations in MMR genes are associated with Lynch syndrome, which have high probability to develop colon cancer. PD-L1, IFN-γ expression and IFN-γ associated immune gene signature are critical factors in determining the sensitivity of anti-PD-1 therapies [8, 9]. It has been reported that MSI subtype of colorectal cancer exhibits an active expression of checkpoint molecules, Wang et al BMC Cancer (2019) 19:605 like PD-L1 and IFN-γ in the tumor microenvironment [13]. The immune-profiles in MSI subtype colon cancer need to be further studied in a globe expression manner
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