Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer

Abstract

BackgroundDickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.MethodsTumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.ResultsElevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.ConclusionsDKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.

Dickkopf proteins in pathological inflammatory diseases

“…Another recent study indicated that elevated expression of DKK1 protein in mouse colorectal cancer (CRC) cells attenuated cytotoxicity of CD8 + T cells by decreasing T‐bet expression and activating GSK3β 36 . In this study, in patients with deficient mismatch repair (dMMR)/microsatellite instability (MSI) CRC, the increased‐serum DKK1 was related to poor prognosis, decreased sensitivity to PD‐1 blockade, and weakened immune status.…”

Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer

“…Those including REG1A, KLK8, KLK12 and MAGEA are up regulated in IVE group, among which REG1A and KLK8 predict poor prognosis in CRC [ 33 , 34 ], while silence of KLK12 and MAGEA can inhibit CRC growth and promote cell death [ 35 , 36 ]. Interestingly, cytoplasmic ASPN have been found to promote cell migration and indicate a poor prognosis in colorectal cancer [ 37 ], and elevated DKK1 expression is associated with recurrence and impairs the response to PD-1 blockade in dMMR CRC [ 38 ], while both of which are down regulated in IVE group. PTF1A has been well studied in pancreatic cancer.…”

Dickkopf-1 is a Prognostic Biomarker and Correlated With Immune Infiltrates in Head and Neck Squamous Cell Carcinoma

“…These results indicate that DKK1 is contributed to the regulation of tumor immune cells. Sui et al reported that DKK 1 impairs the tumor response to PD-1 blockade by inactivating CD8 + T cells in colorectal cancer [14]. Another study demonstrated that metastatic castration-resistant prostate cancer (mCRPC) tumors with high DKK1 expression exhibit a CD8 + T-cell-poor tumor microenvironment in ltrated with immature M0 macrophages and M2 macrophages [31].…”

“…Dysregulation of DKK1 has recently emerged as a potential biomarker of cancer progression and prognosis for several types of malignancies [13]. A recent study reveals that DKK1 impairs the tumor response to PD-1 blockade by inactivating CD8 + T cells in defcient mismatch repair colorectal cancer [14]. Another study shows that upregulation of DKK1 could modulate anti-tumor immune populations within the tumor microenvironment by decreasing CD45 + leukocyte in ltration and reducing NK and CD8 + T cells [15].To summarize, DKK1 had immunoregulatory effects, including promoting Th2 cells response, reducing the functionality of T cells through MDSC modulation and suppressing the proliferation of CD8 + T cells and NK cells, thus contributing to in ammatory response and cancer immune evasion [16].Thus, further research of DKK1 in oncology has garnered a lot of attention.DKK1 has multifaceted functions in the tumor microenvironment.…”