Differential Role of CD318 in Tumor Immunity Affecting Prognosis in Colorectal Cancer Compared to Other Adenocarcinomas

Abstract

Background/Objectives: CD318 (also known as CDCP1) is a transmembrane protein that is overexpressed in many cancers and contributes to tumor progression, invasion, and metastasis by activating SRC family kinases through phosphorylation. Emerging evidence also suggests that CD318 plays a role in modulating the tumor immune microenvironment, although its precise mechanism in tumor progression is still not well understood. Methods: To investigate this, we analyzed the expression and immune-related functions of CD318 using the publicly available data from The Cancer Genome Atlas (TCGA) across colorectal adenocarcinoma (COAD), cervical squamous cell carcinoma (CESC), lung adenocarcinoma (LUAD), and pancreatic adenocarcinoma (PAAD). Results: All four cancers exhibited a high level of CD318 expression. Notably, in CESC, LUAD, and PAAD, plasmin-mediated cleavage of CD318 leads to phosphorylation of SRC and protein kinase C delta (PKCδ), which activates HIF1α and/or p38 MAPK. These downstream effectors translocate to the nucleus and promote the transcriptional upregulation of TGFβ1, fostering an immunosuppressive tumor microenvironment through Treg cell recruitment. In contrast, this signaling cascade appears to be absent in COAD. Instead, our analysis indicate that intact CD318 in COAD interacts with the surface receptors CD96 and CD160, which are found on CD8⁺ T cells and NK cells. Conclusions: This interaction enhances cytotoxic immune responses in COAD by promoting CD8⁺ T cell and NK cell activity, offering a possible explanation for the favorable prognosis associated with high CD318 expression in COAD, compared to the poorer outcomes observed in CESC, LUAD, and PAAD.

Keywords: CDCP1/CD318; PKCδ; SRC; T and NK cells; TGFβ1; overall survival.

Figure 1

Gene ontology, pathway enrichment, and structure of CD318. (A) String analysis of CD318 showing direct and indirect interactions of proteins with CD318. (B) Gene Ontology (GO) enrichment analysis of CD318 involves three aspects: Biological process, Molecular function, and Cellular compartment. (C) Structure of CD318 showing signal peptide, extracellular CUB domains, and intracellular cytoplasmic domain.

Figure 2

mRNA and protein expression of CD318 in multiple cancers. (A) Analysis of CD318 mRNA expression in various cancers compared to their corresponding normal tissues using TCGA database and GEPIA2 tool. (B) Significantly elevated mRNA expression of CD318 in CESC, COAD, LUAD, and PAAD cancer patients compared to normal tissue. (C) Immunohistochemistry images of CD318 protein in CESC, COAD, LUAD, and PAAD and their normal tissue from the human protein atlas. (D) Quantification of relative protein expression of CD318 protein in COAD, LUAD, and PAAD vs. normal tissue. Each dot represents an expression of the sample, where * indicates p ≤ 0.05, and **** indicates p ≤ 0.0001, via t-test. T indicates tumor and N indicates normal tissue.

Figure 3

Correlation between CD318 and SRC/FAK in COAD, CESC, LUAD, and PAAD. (A) Non-significant mRNA correlation of SRC (i) and FAK (ii) with CD318 in COAD. (B) Significant mRNA correlation of SRC (i) and FAK (ii) with CD318 in CESC, LUAD, and PAAD.

Figure 4

Plasmin cleavage of CD318 phosphorylates PKCδ, increasing TGFβ1-mediated immune suppression in CESC and LUAD but not in COAD. (A) Diagram showing that the plasmin cleavage of CD318 phosphorylates PKCδ, activates HIF1α, and phosphorylates p38 MAPK, leading to increased transcription of TGFβ1. (B) mRNA expression of HIF1α (i), MAPK12 (ii), and TGFβ1 (iii). (C) Correlation between CD318 and TGFβ1 in COAD (i), CESC (ii), LUAD (iii), and PAAD (iv) using TISIDB. (D) (i) Heatmap of correlation between CD318 and Treg cells, and correlation of abundance of Treg with CD318 expression in COAD (ii), CESC (iii), and LUAD (iv) using TISIDB.

Figure 5

Prediction of interaction and association of CD96 and CD160 with CD318 in COAD. Docking site identification between CD318 and CD96 (A) and CD318 and CD160 (D) using ClusPro. Heatmap of correlation between CD318 and CD96 (B) and CD160 (E). Spearman correlations of CD318 expression with CD96 expression (C) and CD160 expression (F) in COAD (i), CESC (ii), LUAD (iii), and PAAD (iv) using TISIDB.

Figure 6

Correlation between CD318 and infiltrating CD8+ T cells and NK cells. The heatmap of the correlation of CD318 with CD8+ T cells (A) and NK cells (D) in COAD, CESC, LUAD, and PAAD. (B) (i) Scatter plot of relationship between infiltrating CD8+ T cells and CD318 expression (ii) Abundance of activated CD8+ T cells with CD318 expression in COAD. (C) Relationship between infiltrating CD8+ T cells and CD318 expression in CESC (i), LUAD (ii), and PAAD (iii). (E) (i) Analysis of infiltrating NK cells with CD318 expression and (ii) abundance of CD56^dim NK cells with CD318 expression in COAD. (F) Analysis of infiltrating NK cells with CD318 expression in CESC (i), LUAD (ii), and PAAD (iii).

Figure 7

Prognostic analysis of CD318 in COAD, CESC, LUAD, and PAAD. (A) Analysis of overall survival (OS) with regards to CD318 expression using Kaplan–Meier in COAD (i), CESC (ii), LUAD (iii) and PAAD (iv) using the GEPIA 2 dataset. (B) Survival contribution of CD318 gene in COAD, CESC, LUAD, and PAAD cancers, estimated using Mantel–Cox test. (C) Analysis of clinical relevance of CD318 expression across four cancer types by Z score using Timer 2.0 analytical tool.

Figure 8

Diagram of mechanism of CD318 involving immune cells in COAD vs. CESC, LUAD, and PAAD. COAD has CD8+ T/NK cell-mediated anti-tumor immune response, whereas CESE, LUAD, and PAAD have TGFβ1/Treg cell-mediated immune suppression.