Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment

Abstract

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.

Keywords: DCLK1; cancer stem cells; immunotherapies; microenvironment; tuft cells.

Figure 1

Potential Role of DCLK1 and DCLK1+ Cells in the Intestinal Tumor Microenvironment. DCLK1+ tuft cells (TC) will recruit innate lymphoid type-2 cells (ILC2) by secreting IL-25 which in turn reprograms intestinal stem cells (ISC) through IL4/13-IL4R signaling to express transcription factor POU2F3 leading to TC hyperplasia. In the presence of mutation and inflammation, DCLK1+ TCs can be converted to cancer stem cells (CSC) and initiate a tumor. Under hypoxia, DCLK1+ CSCs may induce angiogenesis by upregulation of HIF-1 and secretion of VEGF. Furthermore, DCLK1+ CSCs promote EMT via the miR-200 family leading to metastatic CSCs (mCSC) with high levels of PD-L1. DCLK1+ CSCs further regulate the immune tumor microenvironment by polarization of M1 macrophages towards an M2 status by secreting IL-6, IL-10 and CXCL12, which leads to inhibition of T-cell proliferation and activation. DCLK1-positive CSCs also express programmed death ligand 1 (PD-L1) expression to inhibit CD8/PD1++ CTL function.