RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer.

RNF43 is a tumor suppressor for various cancers and is considered to drive carcinogenesis when mutated. However, the correlation between RNF43 mutation and colorectal cancer (CRC) immunotherapy remains unreported. We evaluated the role of RNF43 using publicly available data from the Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). In addition, further analysis was performed on an internal validation cohort (hcohort). The mutant profiles of RNF43 were analyzed in 873 Chinese CRC patients. The relationship between clinical pathologic features and RNF43 were analyzed using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics were associated with overall survival using Cox regression and the Kaplan-Meier method. We found that RNF43 mutation was significantly associated with high TMB and high MSI score (all p-values < 0.05) in the MSKCC cohort. Additionally, RNF43 mutation was found to be enriched in MSI instability. Kaplan-Meier survival analysis revealed that patients with RNF43 mutation had better OS compared to RNF43 wild-type (not reached vs. 13 months, HR, 0.12; 95% CI 0.03 to 0.49; P = 0.0034). However, no association was observed between RNF43 and OS in the TCGA cohort (HR, 1.83; 95% CI 0.66 to 5.07; P = 0.2479). Our CRC hcohort confirmed the significance of RNF43 mutation in predicting better clinical outcomes, including ORR (45% vs. 21%, P = 0.0468). RNF43 mutation correlated with a high tumor mutation burden (P < 0.001). The mutation frequency of RNF43 in CRC patients was 8.4% (73/873); RNF43 G659Vfs*41 was found to be the most frequent mutation site. In patients with RNF43 mutations, TP53, KRAS, and TGFBR2 were genes with a high frequency of mutations. Compared with RNF43 wild-type patients, those with RNF43 mutations had a higher TMB score and a greater proportion of MSI-H, but no difference in PD-L1 expression. Moreover, the content of immune-related B cells, CD8+ T cells, neutrophils, and dendritic cells was higher in the RNF43 mutant group than in the wild-type group. Our results suggest that RNF43 mutation may correlate with better OS in CRC patients receiving PD-1/PD-L1 inhibitors. The exact mechanisms underlying RNF43 require further investigation.

Nano-Platelets as an Oxygen Regulator for Augmenting Starvation Therapy Against Hypoxic Tumor.

The restriction of a tumor's energy supply is proven to be an effective means of treatment. Glucose oxidase (GOx), an enzyme that catalyzes the conversion of glucose to glucolactone, producing oxygen and hydrogen peroxide in the process, has proved useful in this regard. However, hypoxia, which is implicated in tumor growth, has been found to mediate resistance to this type of tumor starvation. Here, we describe the design and testing of a platelet membrane mimetic, PMS, consisting of mesoporous silica nanoparticles (MSNs) loaded with metformin (MET) as an inner layer and platelet membranes (PM) as an outer layer that inhibits oxygen consumption by the tumor cells' respiratory pathways and enhances the effectiveness of GOx. MET directly inhibits the activity of complex I in mitochondrial electron transport and is thus a potent inhibitor of cell respiration. PMS target tumor tissue effectively and, once internalized, MET can inhibit respiration. When oxygen is plentiful, GOx promotes glucose consumption, allowing amplification of its effects on tumor starvation. This combination of respiratory suppression by PMS and starvation therapy by GOx has been found to be effective in both targeting tumors and inhibiting their growth. It is hoped that this strategy will shed light on the development of next-generation tumor starvation treatments.

The composition and variation of the BCR CDR3s in gastric cancer.

Gastric cancer (GC) is the fourth most common type of cancer and the second most common cause of cancer-associated mortality worldwide. B cell-associated autoantibodies against tumor-associated antigens are attractive biomarkers for the development of noninvasive serological tests for the early detection of cancer. This is due to their specificity and stability in the sera. In the present study multiplex polymerase chain reaction and Illumina high-throughput sequencing (HTS) was used to study the composition and variation of the B cell receptor (BCR) complimentary-determining region 3 (CDR3) in GC. The peripheral blood, cancer tissues and peri-cancer tissues were included from 7 patients with GC. On average there was a total of 403,959 CDR3 sequences, with 72,367 unique CDR3 nt sequences and 61,709 unique CDR3 aa sequences per sample identified, which are critical for further understanding the BCR repertoire in GC. The details of GC CDR3s may accelerate the screening process for possible new autoantigens and may provide additional information necessary for generating effective B cell targeted diagnosis and therapeutic strategies.