Death receptors 4/5 mediate tumour sensitivity to natural killer cell-mediated cytotoxicity in mismatch repair deficient colorectal cancer.

BACKGROUND: Identifying the target of natural killer (NK) cells in colorectal cancer (CRC) is critical for optimising the clinical use of NK cell-mediated immunotherapy. Mismatch repair deficiency (dMMR) is associated with high immune cell infiltration and MHC Class I defects. Whether dMMR CRC responses to NK cell therapy remains unclear. METHODS: MLH1, DR4, and DR5 knockout cell lines were established using CRISPR-Cas9 system. NK92-MI or NK cell isolated from BABL/C mice were used as effector cells against tumour cells. Inflammatory cytokines secretion by CRC cells was assessed via cytokine analysis. NK-cell-deficient/proficient animal models were used to validate the NK cell sensitivity. RESULTS: We observed that dMMR CRC cells were more sensitive to NK cell-mediated cytotoxicity than were mismatch-repair-proficient (pMMR) CRC cells. In dMMR CRC, Death receptor (DR)4/5 was upregulated and mediated sensitivity to NK cell-mediated cytotoxicity. DR4/5-mediated secretion of interleukin -12 sustained NK cell viability in dMMR CRC. NK cell depletion induced dMMR CRC tumour growth, and NK cell transfer inhibited lung metastasis of dMMR CRC with DR4/5 expression in vivo. TP53 upregulated DR4/DR5 expression in dMMR CRC. CONCLUSIONS: dMMR associated with increased sensitivity to NK cell-mediated cytotoxicity in CRC. DR4/DR5 sensitise dMMR CRC to NK cell-mediated cytotoxicity.

Response to programmed cell death protein 1 antibody in patients with Epstein-Barr virus-associated intrahepatic cholangiocarcinoma.

AIM: Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3+ and CD8+ T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC. METHODS: Patients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured. RESULTS: A total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months. CONCLUSIONS: This study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody.

Predictive value of prognostic nutritional and systemic immune-inflammation indices for patients with microsatellite instability-high metastatic colorectal cancer receiving immunotherapy.

Background: The prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) are indicators of nutritional immune status. They have been reported associated with clinical outcomes of various solid tumors. However, it is unclear whether they can serve as predictors for patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) receiving immunotherapy. Our objective was to study the prognostic value of PNI and SII in these patients. Methods: Seventy-five MSI-H mCRC patients were enrolled in our study. Logistic regression analysis was used to identify features that influenced immunotherapy response. Survival differences between groups of mCRC patients were compared using the Kaplan-Meier method and log-rank test. The independent risk parameters for progression-free survival (PFS) and overall survival (OS) of patients with MSI-H mCRC were established by Cox proportional risk regression analysis. Results: The optimal SII and PNI cutoff values were 409.6 and 51.35. Higher PNI (p = 0.012) and lower high-density lipoprotein cholesterol (HDLC, p = 0.012) were associated with a better immunotherapy response. SII (p = 0.031), cholesterol (CHO) (p = 0.007) and aspartate aminotransferase (AST) (p = 0.031) were independent prognostic factors correlated with OS. Higher PNI (p = 0.012) and lower AST (p = 0.049) were negative predictors of PFS. In addition, patients suffered from immune-related adverse events (irAEs) had a lower SII level (p = 0.04). Conclusion: Higher AST and SII, and lower PNI predict worse outcomes in MSI-H mCRC patients undergoing immunotherapy. Moreover, patients with lower SII before immunotherapy suffered from irAEs more often.

Shared sex hormone metabolism-related gene prognostic index between breast and endometrial cancers.

Aims: As sex hormone-dependent tumors, it remains to be clarified whether there is a common genetic signature and its value between breast and endometrial cancers. The aim of this study was to establish the shared sex hormone metabolism-related gene prognostic index (SHMRGPI) between breast and endometrial cancers and to analyze its potential role in the therapeutic and prognostic assessment of endometrial cancers. Methods: Using transcriptome data from TCGA, tumor-associated gene modules were identified by weighted gene co-expression network analysis, and the intersection of module genes with female sex hormone synthesis and metabolism genes was defined as sex hormone metabolism-related gene. SHMRGPI was established by the least absolute shrinkage and selection operator and Cox regression. Its prognostic value of patients with endometrial cancer was validated, and a nomogram was constructed. We further investigated the relationship between SHMRGPI groups and clinicopathological features, immune infiltration, tumor mutation burden, and drug sensitivity. Results: A total of 8 sex hormone metabolism-related gene were identified as key genes for the construction of prognostic models. Based on SHMRGPI, endometrial cancer patients were divided into high and low SHMRGPI groups. Patients in the low SHMRGPI group had longer overall survival (OS) compared with the high group (P< 0.05). Furthermore, we revealed significant differences between SHMRGPI groups as regards tumor immune cell infiltration, somatic mutation, microsatellite instability and drug sensitivity. Patients with low SHMRGPI may be the beneficiaries of immunotherapy and targeted therapy. Conclusions: The SHMRGPI established in this study has prognostic power and may be used to screen patients with endometrial cancer who may benefit from immunotherapy or targeted therapy.

Exploitation of a shared genetic signature between obesity and endometrioid endometrial cancer.

Aims: The findings in epidemiological studies suggest that endometrioid endometrial cancer (EEC) is associated with obesity. However, evidence from gene expression data for the relationship between the two is still lacking. The purpose of this study was to explore the merits of establishing an obesity-related genes (ORGs) signature in the treatment and the prognostic assessment of EEC. Methods: Microarray data from GSE112307 were utilized to identify ORGs by using weighted gene co-expression network analysis. Based on the sequencing data from TCGA, we established the prognostic ORGs signature, confirmed its value as an independent risk factor, and constructed a nomogram. We further investigated the association between grouping based on ORGs signature and clinicopathological characteristics, immune infiltration, tumor mutation burden and drug sensitivity. Results: A total of 10 ORGs were identified as key genes for the construction of the signature. According to the ORGs score computed from the signature, EEC patients were divided into high and low-scoring groups. Overall survival (OS) was shorter in EEC patients in the high-scoring group compared with the low-scoring group (P < 0.001). The results of the Cox regression analysis showed that ORGs score was an independent risk factor for OS in EEC patients (HR = 1.017, 95% confidence interval = 1.011-1.023; P < 0.001). We further revealed significant disparities between scoring groups in terms of clinical characteristics, tumor immune cell infiltration, and tumor mutation burden. Patients in the low-scoring group may be potential beneficiaries of immunotherapy and targeted therapies. Conclusions: The ORGs signature established in this study has promising prognostic predictive power and may be a useful tool for the selection of EEC patients who benefit from immunotherapy and targeted therapies.

Regorafenib with or without a programmed cell death protein 1 antibody as third-line treatment for microsatellite stable metastatic colorectal cancer.

BACKGROUND: Although the use of regorafenib plus nivolumab demonstrates promising outcomes in patients with refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC), this effect has not been substantiated in other studies. Moreover, a comparison between the outcomes of regorafenib and programmed cell death protein 1 (PD-1) antibody combination therapy and regorafenib monotherapy remains unexplored. In this study, we aimed to assess whether regorafenib and PD-1 antibody combination therapy is superior to regorafenib monotherapy as a third-line treatment for MSS mCRC. METHODS: Patients with MSS mCRC who received regorafenib and PD-1 antibody or regorafenib monotherapy as third-line treatment were eligible for inclusion. RESULTS: In total, 179 patients were enrolled, of which 84 were administered regorafenib combined with a PD-1 antibody and 95 were administered regorafenib monotherapy. Patients administered regorafenib combined with a PD-1 antibody had similar progression-free survival (PFS) as those on regorafenib monotherapy (median PFS was 2.4 months and 1.9 months, respectively, p = 0.086). The administration of regorafenib combined with a PD-1 antibody resulted in significantly longer PFS than that seen with regorafenib monotherapy in both male (5.2 months vs. 2.4 months, p = 0.001) and female (3.9 months vs. 1.8 months, p = 0.037) patients without liver metastasis. Female patients with liver metastasis who were administered regorafenib combined with a PD-1 antibody had shorter PFS than those administered regorafenib monotherapy (1.8 months vs. 2.0 months, p = 0.030). CONCLUSION: Liver metastasis and sex are predictors of survival benefit following the addition of a PD-1 antibody to regorafenib in patients with MSS mCRC.

Diagnostic and prognostic nomograms for bone metastasis in small cell lung cancer.

OBJECTIVE: Patients with bone metastasis (BM) of small cell lung cancer (SCLC) have a poor prognosis. We aimed to identify predictors and prognostic factors in patients with BM of SCLC and construct nomograms to predict BM. METHODS: We retrospectively analyzed 18,187 cases from the Surveillance, Epidemiology, and End Results database reported between 2010 and 2016. Differences in overall survival (OS) and cancer-specific survival (CSS) were evaluated after propensity score matching. Independent predictors for BM and prognostic factors for patients with BM of SCLC were determined using univariate and multivariate regression analyses. Two nomograms were constructed and evaluated using C-statistics. RESULTS: BM was observed in 4014 (22.07%) patients. Kaplan-Meier survival analysis revealed significant differences between BM and non-BM groups. The median OS for patients with and without BM was 6 and 7 months, respectively. The median CSS for patients with and without BM was 9 and 13 months, respectively. Age, sex, tumor size, N stage, chemotherapy, surgery, radiotherapy, and liver/brain/lung metastases were related to BM and independent prognostic factors for OS and CSS. Diagnostic and prognostic nomograms were generated. CONCLUSION: Our nomograms predicted the incidence of BM and the 5-month survival rate of patients with SCLC and BM.

The prognostic value of homeobox B7 expression in patients with hepatocellular carcinoma.

The prognostic role of homeobox B7 (HOXB7) in hepatocellular carcinoma (HCC) is not clearly established. The present study aimed to evaluate the associations among the clinicopathological characteristics, HOXB7 expression, and the overall survival (OS) of patients with HCC. An immunohistochemical analysis was used to detect the expression level of HOXB7. In addition, the association between the expression of HOXB7 and the clinicopathological characteristics of HCC was analyzed. The Kaplan-Meier method was used to calculate the survival rates, and the COX proportional hazards model was used to investigate univariate and multivariate analyses. A total of 80 patients were enrolled in this study. Of the 80 HCC samples, HOXB7 was up-regulated in 28 samples (35.0%). The high HOXB7 expression was significantly associated with OS by univariate Cox regression analysis (HR = 2.0; 95% CI = 1.1-3.4, P = 0.016). The median survival with high HOXB7 expression and low HOXB7 expression was 12.5 months ± 3.7 months versus 32.5 months ± 4.7 months, respectively, as visualized on Kaplan-Meier curves (P = 0.014). After adjusting for possible factors related to survival time after HCC resection, the results suggested that survival time was negatively correlated with high HOXB7 expression (HR = 2.592, 95% CI = 1.283-5.239, P = 0.008). The present data indicate that the HOXB7 expression was negatively associated with survival time after HCC resection. As HOXB7 was a common and readily available measurement in the clinical setting, it was a convenient and feasible way to identify those patients who were at high risk and who had a poor prognosis.