Emerging evidence has revealed that the removal of N-linked glycosylation could enhance PD-L1 detection. However, whether PD-L1 antibodies against different epitopes of PD-L1 antigens responding to deglycosylation has not been characterized. In this study, we compared natural and deglycosylated PD-L1 expression in lung cancer (LuCa) using a panel of PD-L1 antibodies (28–8, CAL10, 73–10 and SP142). We found that removal of N-linked glycosylation markedly enhanced PD-L1 detection when the 28–8, CAL10 and SP142 monoclonal antibodies (mAbs) were used but slightly inhibited PD-L1 detection when the 73–10 mAb was used. Moreover, for the CAL10 and SP142 mAbs, deglycosylated PD-L1 levels showed stronger correlations with the response to anti-PD-1 therapy. Overall, our research provides a comprehensive insight into the application of deglycosylated PD-L1 detection, which expands the clinical significance of this established strategy in LuCa.

The transcription factor zinc finger E-box binding homeobox 1 (ZEB1) is a critical inducer of epithelial mesenchymal transformation (EMT) and plays a robust role in tumor metastasis. It can promote not only the movement and diffusion of tumor cells but also cell stemness, treatment resistance, tumor metastasis and immune escape. The expression of ZEB1 is strictly regulated by a variety of pretranscriptional and posttranscriptional signaling pathways and molecules. Increasing evidence indicates that protein modifications such as methylation and acetylation of ZEB1 can also affect tumor metastasis. More importantly, ZEB1 induces immunosuppressive cells and chemokines into the tumor microenvironment (TME), leading to the formation of a tumor immunosuppressive microenvironment. This review summarizes the regulatory factors involved in ZEB1 expression and its important role. The areas of research covered in this review contribute to providing new thoughts and new treatment insights for targeted ZEB1 therapy of malignant tumors.

Background Immune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear. Methods In this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of angiotensin receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis. Results AGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy. Conclusion Overall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.

Background and Aim:  This study investigated the effects of peripheral administration of ghrelin and PYY_3‐36 on food intake and plasma and tissue fasting and postprandial ghrelin and PYY_3‐36 levels in normal‐weight (NW) and diet‐induced‐obese (DIO) rats.Methods:  In experiment one, NW and DIO rats received a single intraperitoneal injection of saline, PYY_3‐36 or ghrelin; food intake was measured for 4 h. In experiment two, total plasma ghrelin and PYY_3‐36, gastric fundus ghrelin, and ascending colon PYY_3‐36 were measured either after a 20‐h fast or 2 h after refeeding in NW and DIO rats by radioimmunoassay.Results:  Compared to the NW rats, findings in the DIO rats revealed: (i) a reduced sensitivity to both the anorectic effect of exogenous PYY_3‐36 and the orexigenic effect of exogenous ghrelin; (ii) the postprandial plasma ghrelin levels were significantly higher; and (iii) refeeding decreased endogenous plasma ghrelin levels by 53% in the NW rats and 39% in DIO rats. Refeeding increased the plasma PYY_3‐36 level by 58% in the NW rats versus 9% in the DIO rats (P = 0.003).Conclusions:  Compared with regular rats, DIO rats exhibit blunted responses in food intake to exogenous ghrelin and PYY_3‐36. Although endogenous ghrelin and PYY_3‐36 in DIO rats are not altered in the fasting state, their responses to food ingestion are blunted in comparison with regular rats.