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Abstract
BackgroundColon cancer is a malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divided it into different subtypes to facilitate individualized treatment. With the rise in the use of immunotherapy, its value in the field of tumor has begun to emerge. From the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored the same.MethodsCibersort algorithm was used to analyze the level of immune cell infiltration in patients with colon cancer in The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network analysis (WGCNA), Consensus Clustering analysis, Lasso analysis, and univariate Kaplan–Meier analysis were used to screen and verify the hub genes associated with M2 macrophages. Principal component analysis (PCA) was used to establish the M2 macrophage-related score (M2I Score). The correlation between M2I Score and somatic cell variation and microsatellite instability (MSI) were analyzed. Furthermore, the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored.ResultsM2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were identified as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in colon adenocarcinoma was determined based on four hub genes. The M2I Score was positively correlated with the tumor mutation load (TMB). The M2I Score of the group with high instability of microsatellites was higher than that of the group with low instability of microsatellites and microsatellite-stable group. Combined with the Cancer Immunome Atlas database, we concluded that patients with high M2I Scores were more sensitive to programmed cell death protein 1 (PD-1) inhibitors and PD-1 inhibitors combined with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors. The low-rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.ConclusionFour prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score. Patients were divided into two subgroups: high M2I Score group and low M2I Score group. TMB, MSI, and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.
Highlights
According to the latest global cancer data released by the International Agency for Research on Cancer of the World Health Organization in 2020, colon cancer accounted for 10% of the new cases of all malignant tumors, ranking third among all malignant tumors, with deaths reaching nearly 940,000 cases, accounting for 9.4% of all cancer deaths (Siegel et al, 2020)
Because of the importance of macrophages in tumors, tumor therapy strategies targeting macrophages have received considerable attention (Denardo and Ruffell, 2019). In solid tumors, such as gastric cancer and melanoma, high levels of M2 macrophage infiltration are associated with higher expression levels of immune checkpoints, such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), suggesting that macrophages can be used as a potential therapeutic target for tumors (Ju et al, 2020; Kim et al, 2020)
The results showed that the proportion of group with high instability of microsatellites (MSI-H) in the high M2 macrophage infiltration (M2I) Score group was (43%) higher than that in the low M2I Score group (11%), and the chisquare test showed that the difference was statistically significant (Figure 6A)
Summary
According to the latest global cancer data released by the International Agency for Research on Cancer of the World Health Organization in 2020, colon cancer accounted for 10% of the new cases of all malignant tumors, ranking third among all malignant tumors, with deaths reaching nearly 940,000 cases, accounting for 9.4% of all cancer deaths (Siegel et al, 2020). M2 macrophages inhibit the proliferation and activation of T cells by secreting immunosuppressive factors, cytokines, and growth factors, regulate and promote Th2 immune response, promote the growth of tumor cells, participate in tumor angiogenesis, and promote tumor invasion and metastasis (Biswas et al, 2006). Because of the importance of macrophages in tumors, tumor therapy strategies targeting macrophages have received considerable attention (Denardo and Ruffell, 2019) In solid tumors, such as gastric cancer and melanoma, high levels of M2 macrophage infiltration are associated with higher expression levels of immune checkpoints, such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), suggesting that macrophages can be used as a potential therapeutic target for tumors (Ju et al, 2020; Kim et al, 2020). From the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored the same
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