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.

Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response.

Background: Apatinib, a selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR 2), has exhibited modest antitumor efficacy in hepatocellular carcinoma (HCC). We aimed to evaluate the effectiveness and tolerability of apatinib versus sorafenib in patients with advanced HCC.Methods: All patients with advanced HCC who underwent sorafenib or apatinib between January 2016 to December 2017 were retrospectively reviewed. Seventy-two patients received apatinib (26 patients, 500 mg, daily) or sorafenib (46 patients, 400 mg, twice daily) until disease progression or intolerable toxicities. Primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rate (ORR) per modified response evaluation criteria in solid tumors (RECIST), disease control rate (DCR), and safety. Results:The median follow-up was 13.2 (5.7-20.7) months. The 1-year OS for apatinib of 62.0% was comparable to that of sorafenib [64.2%, hazard ratio (HR), 1.15; 95% confidence interval (CI), 0.369-3.58].The median PFS was 4.1 months in the apatinib group (95% CI, 3.2 to 7.4 months) and 3.6 months in the sorafenib group (95% CI, 2.7 to 5.9 months; HR, 1.03; 95% CI, 0.586 to 1.800; P=0.925). The apatinib group exhibited higher ORR (19.2% vs. 2.2%, P=0.012) but similar DCR (57.7% vs. 50%, P=0.530) compared with the sorafenib group. The most common any-grade adverse events in the apatinib and sorafenib groups were hand and foot syndrome (53.8% vs. 50%), hypertension (50% vs. 19.6%), diarrhea (34.6% vs. 28.3%), and elevated transaminase (57.7% vs. 63%).

BACKGROUND:Colorectal cancer with mismatch repair deficiency is usually less aggressive and associated with a lower risk of distant metastasis. Immune checkpoint inhibition, rather than traditional chemoradiotherapy, has shown great advantages in treating such patients. OBJECTIVE:This study aimed to verify the hypothesis that locally very advanced (T4b) colorectal cancer without distant metastases might present with higher probability of mismatch repair deficiency and be more sensitive to neoadjuvant immune checkpoint inhibition.DESIGN: This study was designed as a single-center retrospective observational study. SETTINGS:The study was conducted in a tertiary referral center in China. PATIENTS:The study included patients who were clinically diagnosed with T4bM0 colorectal cancer from 2008 to 2019. MAIN OUTCOME MEASURES:Clinicopathological characteristics, mismatch repair status, and survival outcomes of patients with mismatch repair deficiency were analyzed.

Currently, an increasing number of studies suggest that long non-coding RNAs (lncRNAs) and methylation-regulated lncRNAs play a critical role in the pathogenesis of various cancers including hepatocellular carcinoma (HCC). Therefore, methylated differentially expressed lncRNAs (MDELs) may be critical biomarkers of HCC. In this study, 63 MDELs were identified by screening The Cancer Genome Atlas (TCGA) HCC lncRNAs expression data set and lncRNAs methylation data set. Based on univariate and multivariate survival analysis, four MDELs (AC025016.1, LINC01164, LINC01183 and LINC01269) were selected to construct the survival prognosis prediction model. Through the PI formula, the study indicates that our new prediction model performed well and is superior to the traditional staging method. At the same time, compared with the previous prediction models reported in the literature, the results of time-dependent receiver operating characteristic (ROC) curve analysis show that our 4-MDELs model predicted overall survival (OS) stability and provided better prognosis. In addition, we also applied the prognostic model to Cancer Cell Line Encyclopedia (CCLE) cell lines and classified different hepatoma cell lines through the model to evaluate the sensitivity of different hepatoma cell lines to different drugs. In conclusion, we have established a new risk scoring system to predict the prognosis, which may have a very important guiding significance for the individualized treatment of HCC patients.