The Clinical Significance of Deglycosylated PD-L1 Level Detection Using 28-8 Monoclonal Antibody in Lung Adenocarcinoma.

Purpose: The aim of this study was to explore the clinical significance of deglycosylated PD-L1 level and its correlation with EGFR and ALK mutation in lung adenocarcinoma. Materials and Methods: We estimated the intensity of both native and deglycosylated PD-L1 signals using a 28-8 antibody on lung adenocarcinoma tissue microarray sections. We analyzed the difference in the H-score between tumor and paratumor tissues, as well as that before and after deglycosylation. Correlations between EGFR or ALK status and PD-L1 expression were analyzed. We also evaluated the differences among survival curves. Results: The expression level of PD-L1 in lung adenocarcinoma tissues was significantly higher than that in paratumor tissues (P<0.0001). Deglycosylation significantly enhanced the detection of PD-L1 in tumor tissues (P<0.0001). There was no statistical significance between the signal intensity of deglycosylated PD-L1 and the survival of patients (P=0.9099). However, the response to deglycosylation of PD-L1 was significantly correlated with the survival of patients with stage N1-N3 (P=0.0435) and stage T3-T4 (P=0.0366) and male patients (P=0.0258). A statistical trend was found in the correlation between the response to deglycosylation of PD-L1 and the survival of patients with grade II-III plus grade III (P=0.0973). Correlation between EGFR or ALK status and the expression of PD-L1 was not found (P>0.05). Conclusion: PD-L1 deglycosylation enhances the detection of PD-L1 when utilizing a 28-8 antibody. Moreover, the response to deglycosylation of PD-L1 may predict the survival of certain patients with lung adenocarcinoma.

SOX2-OT induced by PAI-1 promotes triple-negative breast cancer cells metastasis by sponging miR-942-5p and activating PI3K/Akt signaling.

Triple-negative breast cancer (TNBC) has an aggressive biological behavior and poor outcome. Our published study showed that PAI-1 could induce the migration and metastasis of TNBC cells. However, the underlying mechanism by which PAI-1 regulates TNBC metastasis has not been addressed. Here, we demonstrated that PAI-1 is high expressed in TNBC and promotes TNBC cells tumorigenesis. Using microarray analysis of lncRNA expression profiles, we identified a lncRNA SOX2-OT, which is induced by PAI-1 and could function as an oncogenic lncRNA in TNBC. Mechanistic analysis demonstrated that SOX2-OT acts as a molecular sponge for miR-942-5p to regulate the expression of PIK3CA, ultimately leading to activating PI3K/Akt signaling pathway and promoting TNBC metastasis. Taken together, our findings suggest that SOX2-OT regulates PAI-1-induced TNBC cell metastasis through miR-942-5p/PIK3CA signaling and illustrate the great potential of developing new SOX2-OT-targeting therapy for TNBC patients.

The clinical and immune features of CD14 in colorectal cancer identified via large-scale analysis.

BACKGROUND: Cancer immunotherapies have achieved great progress in colorectal cancer (CRC). However, only a small subset of CRC patients with microsatellite instability (MSI) can obtain benefits from immune checkpoint inhibitors (ICIs). Nearly 85% of all CRC patients have microsatellite-stable (MSS) disease, which does not respond to ICIs. Increasing evidence has revealed that CD14 promotes tumor growth and induces an immunosuppressive environment through CD14+ immunosuppressive cells. However, a systematic exploration of CD14 in CRC is lacking. METHOD: A total of 644 samples with transcriptome data and 566 samples with microarray data were investigated in this study, including TCGA RNA-Seq and GSE39582 microarray. R software was the main tool for graphical work and statistical analysis. RESULTS: CD14 was upregulated in the MSI-H, BRAF-mutant, right-sided disease, and hypermethylation groups. Cases with high CD14 expression were related to the CMS4 subtype and had frequent mutation of driver oncogenes. CD14 expression was associated with the regulation of immune system processes in gene ontology analysis. The cytokine-cytokine receptor interaction was associated with CD14 expression. Moreover, CD14 was associated with high immune and stromal infiltration, and CD14 synergized with immune checkpoints. Additionally, CD14 was involved in immune and inflammatory responses. Finally, high CD14 expression predicted worse outcomes and was an independent negative indicator of prognosis in CRC, which was further confirmed in tissue microarray. CONCLUSION: Our findings indicated that CD14 expression was associated with specific clinical characteristics. High CD14 expression might represent pre-existing immunity and have a high correlation with immune checkpoints. Moreover, CD14 correlated with poor clinical outcomes in CRC. Therefore, the CD14 molecule promises to be a potential target to enhance the immunotherapy of colorectal cancers.

NY-ESO-1 expression in solid tumors predicts prognosis: A systematic review and meta-analysis.

BACKGROUND: New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a member of the cancer testis antigen family. NY-ESO-1 has documented potential as an effective target for cancer immunotherapy. The prognostic value of NY-ESO-1 expression in solid tumors, however, remains controversial because of inconclusive data. METHODS: For this analysis, the Medline, Embase, and Cochrane Library databases were searched up to February 2018 for studies investigating NY-ESO-1 expression in solid tumors and overall survival (OS), progression-free survival (PFS), or disease-free survival (DFS). Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from each study. Pooled HRs and CIs were calculated using the Mantel-Haenszel fixed effects or random effects model. RESULTS: A total of 23 studies were included in the analysis. The combined HR (95% CI) estimates for OS, PFS, and DFS were 1.41 (95% CI: 1.24-1.61; I = 0%), 1.62 (95% CI: 1.42-1.84; I = 17%), and 0.95 (95% CI: 0.56-1.59; I = 57%), respectively. CONCLUSIONS: NY-ESO-1 expression in solid tumors is associated with worse OS and PFS. Studies are still needed to provide more evidence.

Optimizing sequential treatment with anti-EGFR and VEGF mAb in metastatic colorectal cancer: current results and controversies.

Anti-EGFR mAb (cetuximab or panitumumab) and anti-VEGF mAb (bevacizumab) are the two main targeted agents available for RAS wild-type (WT) metastatic colorectal cancer (mCRC) treatment. Nonetheless, three head-to-head clinical trials evaluating anti-EGFR mAb vs -VEGF mAb in first-line treatment failed to conclude a uniform result. Recently, a few small clinical studies revealed that prior use of bevacizumab may impair the effect of cetuximab or panitumumab. Preclinical studies have also suggested that pretreatment with bevacizumab may lead to simultaneous resistance to anti-EGFR mAb. Therefore, we performed this review to summarize the available data regarding the optimal sequential treatment of anti-EGFR and -VEGF mAb for RAS or KRAS WT mCRC and discuss the potential mechanisms that may explain this phenomenon. Primary tumor location and early tumor shrinkage have emerged as new potential prognostic and predictive factors in mCRC. We also collected information to explore whether these factors affect the optimal sequencing of targeted therapy in mCRC. However, definite conclusions cannot be made, and we can only speculate on optimal treatment recommendations based on the contradictory results.

Should anti-EGFR mAbs be discontinued for conversion surgery in untreated right-sided metastatic colorectal cancer? A systematic review and meta-analysis.

BACKGROUND: Previous studies have demonstrated that left-sided tumors have better prognoses than right-sided tumors in RAS wild-type mCRC (metastatic colorectal cancer) patients, while anti-EGFR mAbs appear to have no advantage compared with bevacizumab for right-sided tumors in these patients. Nevertheless, it remains unclear whether primary tumor location affects patients' options for potentially curative resection. METHODS: PubMed, the Cochrane Library, Embase, ASCO, and ESMO conference abstracts were searched. The inclusion criteria were RCT (randomized controlled trials) studies that evaluated the efficacy of anti-EGFR mAbs based on primary tumor location. The outcomes included ORR, ETS, and DpR. ORs for ORR were calculated with 95% confidence intervals by Comprehensive Meta-Analysis, version 2.0. RESULT: Nine studies including nine RCTs were analyzed. Regardless of left- or right-sided tumors, the ORRs for anti-EGFR mAb (left-sided: 80.2%, 95% CI, 47-95%; I2 = 76.9%; right-sided: 46.1%, 95% CI, 39.4-53.0%; I2 = 18.9%) were both higher than the control arm including chemotherapy with or without bevacizumab. The ORs for anti-EGFR mAbs have a significant benefit compared with chemotherapy with or without bevacizumab in left-sided tumors (OR = 2.19, 95% CI, 1.41-3.38; P < 0.001). For right-sided tumors, anti-EGFR mAbs still significantly improved the ORR compared with chemotherapy alone (OR = 1.75, 95% CI, 1.05-2.90; P = 0.03), and the OR numerically favored the anti-EGFR mAbs compared with bevacizumab (OR = 1.281, 95% CI, 0.77-2.12; P = 0.335). The data of ETS and DpR from three RCTs also favored the EGFR antibody irrespective of tumor location. Resection data on differentiating tumor locations is inconclusive. For right-sided tumors, it should be noted that median PFS and OS were comparable for patients who achieved ETS in both treatment arms. CONCLUSIONS: Anti-EGFR mAbs have advantages in the tumor shrinkage regardless of left- or right-sided tumors, which is important for conversion therapy. For right-sided tumors, anti-EGFR mAbs should remain the first choice for potentially curative resection in RAS wild-type mCRC patients. ETS may represent a subgroup of patients with right-sided tumors who might benefit from the anti-EGFR mAb.

FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer: A meta-analysis.

BACKGROUND: The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis. METHODS: RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3. RESULTS: The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients. CONCLUSION: So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.