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Infiltration of Apoptotic M2 Macrophage Subpopulation Is Negatively Correlated with the Immunotherapy Response in Colorectal Cancer.

ABSTRACT: The polarization of tumor-associated macrophages (TAMs) plays a key role in tumor development and immunotherapy in colorectal cancer (CRC) patients. However, the impact of apoptosis on TAM polarization and immunotherapy efficacy in patients with different mismatch repair statuses (MMR) remains unclear. Here, we constructed an atlas of macrophage and found a higher rate of infiltration of M2-like TAM subpopulation in pMMR CRC tumor tissues compared with that in dMMR CRC tumor tissues. Importantly, a lower infiltration rate of M2c-like TAMs was associated with immunotherapy response. The M2 polarization trajectory revealed the apoptosis of M2c-like TAMs in dMMR while the differentiation of M2c-like TAMs in pMMR, implying a higher polarization level of M2 in pMMR. Furthermore, we found that a high expression of S100A6 induces the apoptosis of M2c-like TAMs in dMMR. In conclusion, we identified apoptotic TAM subpopulations in the M2 polarization trajectory and found that apoptosis caused by the high expression of S100A6 reduces their infiltration in tumors as well as the level of M2 polarization and contributes to a favorable immunotherapy response. These findings provide new insights into the potential role of apoptosis in suppressing tumors and enhancing immunotherapeutic efficacy.

SUBMITTER: Liu R

PROVIDER: S-EPMC9569653 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Infiltration of Apoptotic M2 Macrophage Subpopulation Is Negatively Correlated with the Immunotherapy Response in Colorectal Cancer.

Liu Rui R Han Chongyin C Hu Jiaqi J Zhang Baowen B Luo Wei W Ling Fei F

International journal of molecular sciences 20220920 19

The polarization of tumor-associated macrophages (TAMs) plays a key role in tumor development and immunotherapy in colorectal cancer (CRC) patients. However, the impact of apoptosis on TAM polarization and immunotherapy efficacy in patients with different mismatch repair statuses (MMR) remains unclear. Here, we constructed an atlas of macrophage and found a higher rate of infiltration of M2-like TAM subpopulation in pMMR CRC tumor tissues compared with that in dMMR CRC tumor tissues. Importantly ...[more]

PMID: 36232318

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Project description:BackgroundColon cancer is characterized by a sophisticated tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which make up the majority of the stromal cells in TME, participate in tumor development and immune regulation. Further investigations of CAFs would facilitate an in-depth understanding of its role in colon cancer TME.MethodsIn this study, we estimated CAF abundance based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using the Microenvironment Cell Populations-counter (MCP-counter) algorithm. CAF-related genes were identified by differential gene expression analysis combined with weighted gene coexpression network analysis. For further selection, the least absolute shrinkage and selection operator (LASSO)-Cox regression was used, and the prognostic value of the selected gene was confirmed in numerous external cohorts. The function enrichment, immunological characteristics, tumor mutation signature, immunotherapy response, and drug sensitivity of the selected gene were subsequently explored. The bioinformatics analysis results were validated using immunohistochemistry on clinical samples from our institution.ResultsAccording to our findings, cartilage oligomeric matrix protein (COMP) was uncovered as a candidate CAFs-driven biomarker in colon cancer and plays an important role in predicting prognosis in colon cancer. COMP upregulation was associated with enhanced stromal and immune activation, and immune cell infiltration, especially M2 macrophages. Genes that mutated differently between the high- and low-COMP expression subgroups may be correlated with TME change. Following verification, COMP reliably predicted the immunotherapy response and drug response. In addition, our experimental validation demonstrated that COMP overexpression is associated with colon cancer carcinogenesis and is strongly associated with CAFs and M2 macrophage infiltration.ConclusionOur study uncovered that COMP was a key CAFs-driven gene associated with M2 macrophage infiltration and acted as a convincing predictor for prognosis and immunotherapy response in colon cancer patients.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer and the seventh most prevalent cause of cancer-related death worldwide. Tumor microenvironment (TME) has been confirmed to play an crucial role in ESCC progression, prognosis, and the response to immunotherapy. There is a need for predictive biomarkers of TME-related processes to better prognosticate ESCC outcomes.AimTo identify a novel gene signature linked with the TME to predict the prognosis of ESCC.MethodsWe calculated the immune/stromal scores of 95 ESCC samples from The Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm, and identified differentially expressed genes (DEGs) between high and low immune/stromal score patients. The key prognostic genes were further analyzed by the intersection of protein-protein interaction (PPI) networks and univariate Cox regression analysis. Finally, a risk score model was constructed using multivariate Cox regression analysis. We evaluated the associations between the risk score model and immune infiltration via the CIBERSORT algorithm. Moreover, we validated the signature using the Gene Expression Omnibus (GEO) database. Within the ten gene signature, five rarely reported genes were further validated with quantitative real time polymerase chain reaction (qRT-PCR) using an ESCC tissue cDNA microarray.ResultsA total of 133 up-regulated genes were identified as DEGs. Ten prognostic genes were selected based on intersection analysis of univariate COX regression analysis and PPI, and consisted of C1QA, C1QB, C1QC, CD86, C3AR1, CSF1R, ITGB2, LCP2, SPI1, and TYROBP (HR>1, p<0.05). The expression of 9 of these genes in the tumor samples were significantly higher compared to matched adjacent normal tissue based on the GEO database (p<0.05). Next, we assessed the ability of the ten-gene signature to predict the overall survival of ESCC patients, and found that the high-risk group had significantly poorer outcomes compared to the low-risk group using univariate and multivariate analyses in the TCGA and GEO cohorts (HR=2.104, 95% confidence interval:1.343-3.295, p=0.001; HR=1.6915, 95% confidence interval:1.053-2.717, p=0.0297). Additionally, receiver operating characteristic (ROC) curve analysis demonstrated a relatively sensitive and specific profile for the signature (1-, 2-, 3-year AUC=0.672, 0.854, 0.81). To identify the basis for these differences in the TME, we performed correlation analyses and found a significant positive correlation with M1 and M2 macrophages and CD8+ T cells, as well as a strong correlation to M2 macrophage surface markers. A nomogram based on the risk score and select clinicopathologic characteristics was constructed to predict overall survival of ESCC patients. For validation, qRT-PCR of an ESCC patient cDNA microarray was performed, and demonstrated that C1QA, C3AR1, LCP2, SPI1, and TYROBP were up-regulated in tumor samples and predict poor prognosis.ConclusionThis study established and validated a novel 10-gene signature linked with M2 macrophages and poor prognosis in ESCC patients. Importantly, we identified C1QA, C3AR1, LCP2, SPI1, and TYROBP as novel M2 macrophage-correlated survival biomarkers. These findings may identify potential targets for therapy in ESCC patients.

Dataset Information

Infiltration of Apoptotic M2 Macrophage Subpopulation Is Negatively Correlated with the Immunotherapy Response in Colorectal Cancer.

Publications

Infiltration of Apoptotic M2 Macrophage Subpopulation Is Negatively Correlated with the Immunotherapy Response in Colorectal Cancer.

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