Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

Abstract

Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer-initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients, respectively, from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1 was strongly linked to infiltration of multiple immune cell types, especially TAMs and Treg, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer, which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients.

Cancer Stemness Meets Immunity: From Mechanism to Therapy

“…On the other hand, CSCs can shape a specific TME by their regulation of immune cells. For instance, the expression of CSC marker and regulator doublecortin-like kinase 1 ( Westphalen et al, 2014 ) correlates positively with abundance of TAMs and regulatory T cells (T-reg cells) and elevated expression of factors that inhibit CD8 + T cell activity ( Wu et al, 2020 ). CKLF-like MARVEL transmembrane-domain-containing 6, which is expressed on cancer cell plasma membranes, can enhance CSC stemness via the WNT/β-catenin pathway, suppress anti-tumor immunity via programmed death-ligand 1 (PD-L1) upregulation, and reduce CD8 + and CD4 + T cells in many types of cancer, including squamous cell carcinoma of the head and neck (SCCHN) ( Chen et al, 2020a ), melanoma, and breast cancer ( Burr et al, 2017 ; Mezzadra et al, 2017 ).…”

DCK is a promising prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

“…Second, the correlation coefficients were not very strong. In fact, when analyzing the relationship between gene levels and TIICs, the correlation coefficients were mostly uncorrelated or had a weak and moderate correlation, and strong correlations were rare [22,24]. Third, we only used public datasets, further identified by our HCC patient profiles, and the detailed relationship should be confirmed by in vitro or animal experiments.…”

“…Additionally, the correlations among DCK expression and different gene markers of TIICs, like T cells, B cells, tumor-associated macrophages (TAMs), monocytes, M1 and M2 macrophages, natural killer (NK) cells, neutrophils, dendritic cells (DCs), T helper (Th) cells, T helper 17 (Th17) cells, follicular helper T (Tfh) cells, Tregs, and exhausted T cells, were analyzed. The marker genes of TIICs were reported as previous study [22].…”

<p>An Iron Metabolism-Related <em>SLC22A17</em> for the Prognostic Value of Gastric Cancer</p>

“…Li et al found that CD4+ and CD8+ T cell expression was a predictive indicator of gastric cancer prognosis. 36 Previous reports showed that the infiltration of macrophages, 37 dendritic cells, 38 neutrophils, 39 neutrophils 40 and B cells 41 is directly associated with tumour invasion and clinical outcomes in gastric cancer.…”