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Review
. 2020 Dec 17;12(12):3801.
doi: 10.3390/cancers12123801.

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

Zhiyun Cao  1   2   3 , Nathaniel Weygant  1   2   3 , Parthasarathy Chandrakesan  4   5   6 , Courtney W Houchen  4   5   6 , Jun Peng  1   2   3 , Dongfeng Qu  4   5   6
Affiliations
Review

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

Zhiyun Cao et al. Cancers (Basel). .

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.

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Conflict of interest statement

C.W.H., D.Q., and N.W. are inventors on a patent for CBT-15 DCLK1-targeted monoclonal antibodies. C.W.H. is an inventor on a patent for CBT-511 DCLK1-targeted CAR-T. C.W.H. is an inventor on a patent for nanoparticle-encapsulated DCLK1-targeted siRNAs.

Figures

Figure 1
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.
See this image and copyright information in PMC

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