Expression and prognostic roles of PRDXs gene family in hepatocellular carcinoma.

BACKGROUND: As the fourth leading cause of cancer-related death in the world, the therapeutic effect and 5-year overall survival of hepatocellular carcinoma (HCC) are not optimistic. Previous researches indicated that the disorder of PRDXs was related to the occurrence and development of cancers. METHODS: In this study, PRDXs were found in various tumor cell lines by CCLE database analysis. The analysis results of UALCAN, HCCDB and Human Protein Atlas databases showed the expression of PRDXs mRNA and protein in HCC tissues was dysregulated. Besides, UALCAN was used to assess the correlations between PRDXs mRNA as well as methylation levels and clinical characterization. RESULTS: High expression of PRDX1 or low expression of PRDX2/3 suggested poor prognosis for HCC patients which was demonstrated by Kaplan-Meier Plotter. The genetic alterations and biological interaction network of PRDXs in HCC samples were obtained from c-Bioportal. In addition, LinkedOmics was employed to analyze PRDXs related differentially expressed genes, and on this basis, enrichment of KEGG pathway and miRNAs targets of PRDXs were conducted. The results indicated that these genes were involved in several canonical pathways and certain amino acid metabolism, some of which may effect on the progression of HCC. CONCLUSIONS: In conclusion, the disordered expression of some PRDX family members was associated with the prognosis of HCC patients, suggesting that these PRDX family members may become new molecular targets for the treatment and prognosis prediction of HCC.

Albumin-based co-loaded sonosensitizer and STING agonist nanodelivery system for enhanced sonodynamic and immune combination antitumor therapy.

STING agonists can activate natural and adaptive immune responses, and are expected to become a new type of immunotherapy drug for tumor therapy. However, how to target deliver STING agonists to tumor tissues is a key factor affecting the efficacy of tumor treatment. Sonodynamic therapy (SDT) has become a research hotspot in the field of cancer treatment due to its non-invasive, spatiotemporally controllable, and high tissue penetration capabilities. Therefore, how to choose the appropriate drug delivery strategy, build a suitable drug delivery system to co-deliver photosensitizers and STING agonists, is a challenge faced in the tumor treatment. In this study, we developed an albumin-based nanodelivery system named FA-ICG&MnOx@HSA that co-loaded the sonosensitizers indocyanine green (ICG) and manganese oxide (MnOx). This approach achieved folate receptor-targeting mediated tumor delivery and tumor microenvironment (TME)-responsive release facilitated by high levels of glutathione (GSH) and hydrogen peroxide (H2O2), which catalyze oxygen generation to potentiate SDT efficacy in killing tumors and inducing immunogenic cell death (ICD). Simultaneously, the released Mn2+ acted as a STING agonist promoting dendritic cell maturation, IFN-ß production, and proliferation of T cells. Ultimately, this albumin based co-loaded sonosensitizer and STING agonist demonstrated promising potential for advancing tumor treatment.

SPI1+CD68+ macrophages as a biomarker for gastric cancer metastasis: a rationale for combined antiangiogenic and immunotherapy strategies.

BACKGROUND: Tumor-associated macrophages (TAMs) have been demonstrated to be associated with tumor progression. However, the different subpopulations of TAMs and their roles in gastric cancer (GC) remain poorly understood. This study aims to assess the effects of Spi-1 proto-oncogene (SPI1)+CD68+ TAMs in GC. METHODS: The distribution of SPI1+CD68+ TAMs in GC tissue was estimated by immunohistochemistry, immunofluorescence, and flow cytometry. Single-cell transcriptome analysis and multiplex fluorescence immunohistochemistry were applied to explore the role of SPI1+CD68+ TAMs in an immune contexture. SPI1 overexpression or knockdown cells were constructed to evaluate its role in macrophage polarization and angiogenesis in vitro and in vivo. Chromatin immunoprecipitation was used to verify the mechanism of SPI1 transcriptional function. The effect of combined antiangiogenic and immunotherapy was further validated using mouse peritoneal metastasis models. RESULTS: Single-cell transcriptome analysis and immunohistochemistry demonstrated that SPI1 was expressed in macrophages, with a higher enrichment in metastatic lesions than in primary tumors. Higher SPI1+CD68+ TAMs infiltration was associated with poor overall survival. Mechanically, SPI1 promoted the M2-type macrophage polarization. SPI1 could bind to the promoter of vascular endothelial growth factor A and facilitate angiogenesis. Moreover, the level of SPI1+CD68+ TAMs infiltration was closely related to the efficacy of immunotherapy, especially when combined with antiangiogenic therapy. CONCLUSIONS: The present study showed that SPI1+CD68+ TAMs are a promising biomarker for predicting prognosis, antiangiogenic drug sensitivity, and combination target of immunotherapy in patients with GC.

Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer.

Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces immune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients. PUM1 positively regulates PD-L1 expression and PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1. PUM1 inhibits the anti-tumor activity of T cells through the PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy.