Abstract
Little is known about the immunoediting process in precancerous lesions. We explored this aspect of benign colorectal adenomas with a descriptive analysis of the immune pathways and immune cells whose regulation is linked to the morphology and size of these lesions. Two series of polypoid and nonpolypoid colorectal adenomas were used in this study: 1) 84 samples (42 lesions, each with matched samples of normal mucosa) whose gene expression data were used to quantify the tumor morphology- and size-related dysregulation of immune pathways collected in the Molecular Signature Database, using Gene Set Enrichment Analysis; 2) 40 other lesions examined with immunohistochemistry to quantify the presence of immune cells in the stromal compartment. In the analysis of transcriptomic data, 429 immune pathways displayed significant differential regulation in neoplasms of different morphology and size. Most pathways were significantly upregulated or downregulated in polypoid lesions versus nonpolypoid lesions (regardless of size). Differential pathway regulation associated with lesion size was observed only in polypoid neoplasms. These findings were mirrored by tissue immunostaining with CD4, CD8, FOXP3, MHC-I, CD68, and CD163 antibodies: stromal immune cell counts (mainly T lymphocytes and macrophages) were significantly higher in polypoid lesions. Certain markers displayed significant size-related differences regardless of lesion morphology. Multivariate analysis of variance showed that the marker panel clearly discriminated between precancerous lesions of different morphologies and sizes. Statistical analysis of immunostained cell counts fully support the results of the transcriptomic data analysis: the density of infiltration of most immune cells in the stroma of polypoid precancerous lesions was significantly higher than that observed in nonpolypoid lesions. Large neoplasms also have more immune cells in their stroma than small lesions. Immunoediting in precancerous colorectal tumors may vary with lesion morphology and stage of development, and this variability could influence a given lesion’s trajectory to cancer.
Highlights
The immune system plays a Janus-like role in the development and progression of cancer, exerting tumor-promoting and tumor-suppressive effects
gene set enrichment analysis (GSEA) of our transcriptomic data using all the collections in the Molecular Signatures Database (MSigDB) revealed enrichment for immune-related pathways in the set of genes differentially expressed in the two morphologic classes of lesions
Serrated histology is a common feature of nonpolypoid lesions, those located in the proximal colon [48], but this factor had no effect on our findings since all but one of the lesions we studied were conventional adenomas (Table 4)
Summary
The immune system plays a Janus-like role in the development and progression of cancer, exerting tumor-promoting and tumor-suppressive effects This duality is the basis of the process known as immunoediting, whereby the immune system shapes (or edits) the evolution of tumorigenesis, qualitatively and quantitatively [1]. The mechanisms underlying the equilibrium phase are of particular interest This state of relative dormancy is typical of the benign, preinvasive stages of tumorigenesis, and it can keep malignancy at bay for years—up to two decades in some cases of colorectal neoplasia [2, 3, 4]. The incidence of precancerous colorectal lesions and/or of “interval” cancers (those occurring before the followup colonoscopy) can be reduced by chemopreventive interventions with aspirin or other nonsteroidal anti-inflammatory drugs, which alter the tumor microenvironment, rendering it more conducive to the elimination of nascent tumors or the arrest or suppression of the growth of larger lesions [5, 6]
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