Abstract
The tumor environment is of vital importance for the incidence and development of colorectal cancer. Increasing evidence in recent years has elaborated the vital role of the tumor environment in cancer subtype classification and patient prognosis, but a comprehensive understanding of the colorectal tumor environment that is purely dependent on the stromal compartment is lacking. To decipher the tumor environment in colorectal cancer and explore the role of its immune context in cancer classification, we performed a gene expression microarray on the stromal compartment of colorectal cancer and adjacent normal tissues. Through the integrated analysis of our data with public gene expression microarray data of stromal and epithelial colorectal cancer tissues processed through laser capture microdissection, we identified four highly connected gene modules representing the biological features of four tissue compartments by applying a weighted gene coexpression network analysis algorithm and classified colorectal cancers into three immune subtypes by adopting a nearest template prediction algorithm. A systematic analysis of the four identified modules mainly reflected the close interplay between the biological changes of intrinsic and extrinsic characteristics at the initiation of colorectal cancer. Colorectal cancers were stratified into three immune subtypes based on gene templates identified from representative gene modules of the stromal compartment: active immune, active stroma, and mixed type. These immune subtypes differed by the immune cell infiltration pattern, expression of immune checkpoint inhibitors, mutation landscape, extent of mutation burden, extent of copy number burden, prognosis and chemotherapeutic sensitivity. Further analysis indicated that activation of the NF-kB signaling pathway was the major mechanism causing the no immune infiltration milieu in the active stroma subtype and that inhibitors of the NF-kB signaling pathway could be candidate drugs for treating patients with an active stroma. Overall, these results suggest that characterizing colorectal cancer by the tumor environment is of vital importance in predicting patients' clinical outcomes and helping guide precision and personalized treatment.
Highlights
Colorectal cancer is the third most common cancer and ranks second in terms of cancer-related mortality [1]
Given the recently reported evidence that a high burden of copy number loss is positively related to anti-CTLA-4 blockade resistance [49, 50], we explored copy number alterations between these distinct immune groups
No studies have systematically elaborated on the molecular interaction patterns of the epithelium and stroma during colorectal cancer initiation
Summary
Colorectal cancer is the third most common cancer and ranks second in terms of cancer-related mortality [1]. The current treatment dilemma underscores the critical need to improve colorectal cancer classification with distinct molecular features and survival outcomes for reasonable clinical treatment decisions. The depiction of a transcriptome map of the altered biological processes in the epithelial and stromal compartments will allow investigators to comprehensively understand the mechanism of cancer initiation and the complex coevolving relationships between the intrinsic and extrinsic factors of tumors [3] and help in the detection of druggable epithelial–stromal crosstalk targets [4]. The major changes in the biological features of the epithelial and stromal compartments between colorectal cancer and adjacent normal tissues remain poorly understood. A systematic analysis of the different compartments of colorectal tissues is needed to better understand the mechanisms of tumor initiation
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