During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.

Colorectal cancer (CRC) screening can effectively reduce disease-related mortality by detecting CRC at earlier stages. We have previously demonstrated that the presence of SDC2 methylation in stool DNA is significantly associated with the occurrence of CRC regardless of clinical stage. The aim of this study was to evaluate the clinical performance of stool DNA-based SDC2 methylation test for CRC. Aberrant SDC2 methylation in stool-derived DNA was measured by linear target enrichment (LTE)-quantitative methylation-specific real-time PCR (qMSP). Duplicate reactions of meSDC2 LTE-qMSP test were performed for stool samples obtained from CRC patients representing all stages (0–IV) and asymptomatic individuals who were subsequently underwent colonoscopy examination. To determine the diagnostic value of test in CRC and control groups, sensitivity and specificity were evaluated by receiver operating characteristic curve analysis. Of 585 subjects who could be evaluated, 245 had CRC, 44 had various sizes of adenomatous polyps, and 245 had negative colonoscopy results. Stool DNA-based meSDC2 LTE-qMSP showed an overall sensitivity of 90.2% with AUC of 0.902 in detecting CRC (0–IV) not associated with tumor stage, location, sex, or age (P > 0.05), with a specificity of 90.2%. Sensitivity for detecting early stages (0-II) was 89.1% (114/128). This test also detected 66.7% (2/3) and 24.4% (10/41) of advanced and non-advanced adenomas, respectively. Results of this study validated the capability of stool DNA based-SDC2 methylation test by LTE-qMSP for early detection of CRC patient with high specificity. ClinicalTrials.gov, NCT03146520 , Registered 10 May 2017, Retrospectively registered; however, control arm was prospectively registered.

Colorectal cancer (CRC) screening is the most efficient strategy to reduce disease-related mortality. Frequent aberrant DNA methylation is known to occur in selected genes and early during CRC development, which has emerged as a new epigenetic biomarker for early detection of CRC. Previously, we reported that we identified that CpG sites of SDC2 were aberrantly methylated in tumor tissues of most CRC patients through comprehensive methylation analysis and demonstrated a high potential of quantification of SDC2 methylation in blood for early detection of colorectal cancer. In this study, we aim to investigate the feasibility of quantifying SDC2 methylation in stool DNA for the early detection of CRC. The objective of this study was to confirm a high frequency of SDC2 methylation in tumor tissues at various stages of CRC and investigate the feasibility of a quantitative test for SDC2 methylation in fecal DNA by highly sensitive and accurate real-time PCR for early detection of CRC. Bisulfite-pyrosequencing assay was performed to measure the SDC2 methylation status in tissue samples. For methylation analysis in stool DNA, a highly sensitive and accurate method was applied which implements consecutive two rounds of PCR consisting of unidirectional linear target enrichment (LTE) of SDC2 and quantitative methylation-specific real time PCR (qMSP) for SDC2, named as meSDC2 LTE-qMSP assay. Its limit of detection was 0.1% methylation (corresponding to ~ 6 copies in total ~ 6200 genome copies). Positive SDC2 methylation was observed in 100% of primary tumors, 90.6% of adenomatous polyps, 94.1% of hyperplastic polyps, and 0% of normal tissues. SDC2 methylation level also significantly (P < 0.01) increased according to the severity of lesions. In stool DNA test for SDC2 methylation by LTE-qMSP comparing CRC patients with various stages (I to IV) (n = 50) and precancerous lesions (n = 21) with healthy subjects (n = 22), the overall sensitivity was 90.0% for detecting CRC and 33.3% for detecting small polyps, with a specificity of 90.9%. Taken together, our result indicates that stool DNA-based SDC2 methylation test by LTE-qMSP is a potential noninvasive diagnostic tool for early detection of CRC.

Introduction: Colorectal cancer is one of the most common malignancies in the world, and it exhibits differences in incidence, pathogenesis, molecular pathways, and outcome depending on the location of the tumor. Differences in the microbiome, clinical characteristics, and chromosomal and molecular characteristics have been reported between the right and left side of the colon. Areas covered: This review focuses on the latest developments in epidemiological and chromosomal and molecular studies, which have enhanced our understanding on the underlying genetic and immunological differences between the right-sided colon and the left-sided colorectum in metastatic colorectal cancer. Expert commentary: The numerous findings regarding differences between right- and left-sided colon cancers should have an impact on colorectal cancer screening and therapy. The location of the colorectal cancer should be considered before group stratification into genetic, clinical, and especially chemotherapy trials. A more tailored approach to colon cancer treatment would be highly desirable if future trials further support the hypothesis of two distinct tumor entities.