Tumor Microenvironment Heterogeneity-Based Score System Predicts Clinical Prognosis and Response to Immune Checkpoint Blockade in Multiple Colorectal Cancer Cohorts

Abstract

Despite immune checkpoint blockade (ICB) therapy contributed to significant advances in cancer therapy, only a small percentage of patients with colorectal cancer (CRC) respond to it. Identification of these patients will facilitate ICB application in CRC. In this study, we integrated multiple CRC cohorts (2,078 samples) to construct tumor microenvironment (TME) subtypes using TME indices calculated by CIBERSORT and ESTIMATE algorithms. Furthermore, a surrogate quantitative indicator, a tumor microenvironment immune gene (TMEIG) score system, was established using the key immune genes between TME clusters 1 and 2. The subsequent analysis demonstrated that TME subtypes and the TMEIG score system correlated with clinical outcomes of patients in multiple CRC cohorts and exhibited distinct immune statuses. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that patients with low TMEIG scores were more likely to benefit from ICB therapy. A study on two ICB cohorts (GSE78220 and IMvigor210) also validated that patients with low TMEIG scores exhibited higher ICB response rates and better prognoses after ICB treatment. The biomarker evaluation module on the TIDE website revealed that the TMEIG score was a robust predictive biomarker. Moreover, differential expression analysis, immunohistochemistry, qPCR experiments, and gene set prioritization module on the TIDE website demonstrated that the five genes that constitute the TMEIG score system (SERPINE1, FABP4, SCG2, CALB2, and HOXC6) were closely associated with tumorigenesis, immune cells, and ICB response indices. Finally, TMEIG scores could accurately predict the prognosis and ICB response of patients with CRC. SERPINE1, FABP4, SCG2, CALB2, and HOXC6 might be potential targets related to ICB treatment. Furthermore, our study provided new insights into precision ICB therapy in CRC.

Pan-cancer analysis of SERPINE family genes as biomarkers of cancer prognosis and response to therapy

“…Wang et al applied five genes, including SERPINE1, to construct a tumor microenvironment immune gene (TMEIG) score system, which can accurately predict the prognosis and immune checkpoint blockade response of colorectal cancer patients. Meanwhile, SERPINE1 may be a potential target related to immunotherapy ( Wang et al, 2022 ). Smirnova et al suggested that SERPINE2 is required in the extracellular milieu of tumors where it acts in multiple ways to regulate tumor matrix deposition, thereby controlling tumor cell dissemination in breast cancer ( Smirnova et al, 2016 ).…”

HOXC6: A promising biomarker linked to an immunoevasive microenvironment in colorectal cancer based on TCGA analysis and cohort validation

“…The “cytokine–cytokine receptor interaction” pathway was also remarkably concentrated in HOXC6 . However, the predictive capacity of the model and the relationship among the five genes have not been verified in patients with CRC [ 50 ]. Another study suggested that HOXC6 may affect the immune microenvironment and promote tumor evolution by adjusting the EMT signaling pathway in gliomas.…”

A comprehensive multi-omics analysis identifies a robust scoring system for cancer-associated fibroblasts and intervention targets in colorectal cancer

“…The transcriptome data of above five cohorts were the microarray data from GPL570 platform. The method of merging multiple data sets and the procedure of removing batch effects were carried out as reported in our previous study (Wang et al 2022a ).The transcriptome data (FPKM) and clinical information of the TCGA COAD cohort were downloaded from the UCSC website (Navarro Gonzalez et al 2021 ). Then FPKM was converted to transcripts per kilobase million (TPM) and further log-2 transformed in next analysis.…”