The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.

Background: Epithelial to mesenchymal transition (EMT) in alveolar epithelial cells (AECs) has been widely observed in patients suffering interstitial pulmonary fibrosis. In vitro studies have also demonstrated that AECs could convert into myofibroblasts following exposure to TGF-β1. In this study, we examined whether EMT occurs in bleomycin (BLM) induced pulmonary fibrosis, and the involvement of bronchial epithelial cells (BECs) in the EMT. Using an α-smooth muscle actin-Cre transgenic mouse (α-SMA-Cre/R26R) strain, we labelled myofibroblasts in vivo. We also performed a phenotypic analysis of human BEC lines during TGF-β1 stimulation in vitro.

CMTM6, a regulator of PD-L1 expression, also modulates tumor immunity. Little is known about the function of CMTM6 and its mechanism of action in head and neck squamous cell carcinoma (HNSCC). In this study, we found by IHC analysis that CMTM6 overexpression predicted a poor prognosis for patients with HNSCC. We discovered that CMTM6 expression was correlated with increased activity through the Wnt/β-catenin signaling pathway, which is essential for tumorigenesis, maintenance of cancer stem cells (CSC), and the epithelial-to-mesenchymal transition (EMT) characteristic of multiple cancers. We used short hairpin RNA to eliminate expression of CMTM6, which led, in HNSCC cells, to reduced expression of nuclear β-catenin as well as inhibition of stem cell–like properties, TGFβ-induced EMT, and cell proliferation. Consistent with these results, we identified a significant positive correlation between expression of CMTM6 and EMT- and CSC-related genes in The Cancer Genome Atlas (TCGA). We found positive correlations for both RNA and protein between expression of CMTM6 and immune checkpoint components. CMTM6 silencing–induced PD-L1 downregulation delayed SCC7 tumor growth and increased CD8+ and CD4+ T-cell infiltration. The proportions of PD-1+, TIM-3+, VISTA+, LAG-3+, and B7-H3+ exhausted T cells were decreased significantly in the CMTM6 knockdown group. CMTM6 thus regulates stemness, EMT, and T-cell dysfunction and may be a promising therapeutic target in the treatment of HNSCC.

Immunosuppression is common in head and neck squamous cell carcinoma (HNSCC). In previous studies, the TIGIT/CD155 pathway was identified as an immunecheckpoint signaling pathway that contributes to the "exhaustion" state of infiltrating T cells. Here, we sought to explore the clinical significance of TIGIT/CD155 signaling in HNSCC and identify the therapeutic effect of the TIGIT/CD155 pathway in a transgenic mouse model. TIGIT was overexpressed on tumor-infiltrating CD8 þ and CD4 þ T cells in both HNSCC patients and mouse models, and was correlated with immune-checkpoint molecules (PD-1, TIM-3, and LAG-3). TIGIT was also expressed on murine regulatory T cells (Treg) and correlated with immune suppression. Using a human HNSCC tissue microarray, we found that CD155 was expressed in tumor and tumor-infiltrating stromal cells, and also indicated poor overall survival.Multispectral IHC indicated that CD155 was coexpressed with CD11b or CD11c in tumor-infiltrating stromal cells. Anti-TIGIT treatment significantly delayed tumor growth in transgenic HNSCC mouse models and enhanced antitumor immune responses by activating CD8 þ T-cell effector function and reducing the population of Tregs. In vitro coculture studies showed that anti-TIGIT treatment significantly abrogated the immunosuppressive capacity of myeloid-derived suppressor cells (MDSC), by decreasing Arg1 transcripts, and Tregs, by reducing TGFb1 secretion. In vivo depletion studies showed that the therapeutic efficacy by anti-TIGIT mainly relies on CD8 þ T cells and Tregs. Blocking PD-1/PD-L1 signaling increased the expression of TIGIT on Tregs. These results present a translatable method to improve antitumor immune responses by targeting TIGIT/CD155 signaling in HNSCC.

The mortality rate of elderly patients with Coronavirus Disease 2019 (COVID-19) was significantly higher than the overall mortality rate. However, besides age, leading death risk factors for the high mortality in elderly patients remain unidentified. This retrospective study included 210 elderly COVID-19 patients (aged ≥ 65 years), of whom 175 patients were discharged and 35 died. All deceased patients had at least one comorbidity. A significantly higher proportion of patients in the deceased group had cardiovascular diseases (49% vs. 20%), respiratory diseases (51% vs. 11%), chronic kidney disease (29% vs. 5%) and cerebrovascular disease (20% vs. 3%) than that in the discharged group. The median levels of C-reactive protein (125.8mg/L vs. 9.3mg/L) and blood urea nitrogen (7.2mmol/L vs. 4.4mmol/L) were significantly higher and median lymphocyte counts (0.7×10 9 /L vs. 1.1×10 9 /L) significantly lower in the deceased group than those in the discharged group. The survival curve analysis showed that higher C-reactive protein (≥5mg/L) plus any other abnormalities of lymphocyte, blood urea nitrogen or lactate dehydrogenase significantly predicted poor prognosis of COVID-19 infected elderly patients. This study revealed that the risk factors for the death in these elderly patients included comorbidities, increased levels of C-reactive protein and blood urea nitrogen, and lymphopenia during hospitalization.

Background Partial epithelial mesenchymal transition (p-EMT) was found to play a potential role in the initial stage of metastasis in human head and neck squamous cell carcinoma (HNSCC). Some long noncoding RNAs (lncRNAs) have been reported to function as promoters or inhibitors of cancer metastasis. This study aimed to identify p-EMT-related lncRNAs in HNSCC. Methods Differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DEGs) in HNSCC obtained from The Cancer Genome Atlas (TCGA) were screened out by using the “edgeR” package. DE-lncRNAs in the Oral squamous cell carcinoma (OSCC) lncRNA microarray dataset GSE84805 were screened out by using the “limma” package. Slug-related lncRNAs were determined by Pearson correlation analysis (|Pearson correlation coefficient| ≥ 0.4, p < 0.01) based on TCGA. Survival analysis were performed for the overlapping DE-lncRNAs by using the “Survival” package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to predict the potential functions of MYOSLID. RT-qPCR and In Site Hybridization (ISH) were used to explore the MYOSLID expression and its clinical significance in HNSCC specimens. Immunohistochemical staining, siRNA, wound healing assay, transwell assay, and western blot were used to explore the biological function and potential molecular mechanisms. Results MYOSLID was identified as a Slug-related lncRNA and with prognostic value among the 9 overlapping DE-lncRNAs. GO and KEGG analyses revealed that MYOSLID was closely related to important biological processes and pathways that regulate cancer metastasis. The results of univariate and multivariate Cox regression analysis based on TCGA and HNSCC tissue microarray data suggested MYOSLID was an independent prognostic factor. MYOSLID expression in HNSCC was closely correlated with Slug, PDPN and LAMB3. The knockdown of MYOSLID in OSCC cell line significantly inhibited cell migration and invasion compared to those in the control cells. In addition, the knockdown of MYOSLID significantly reduced Slug, PDPN and LAMB3 expression levels. However, the knockdown of MYOSLID had no effect on the expression levels of the EMT biomarkers E-cadherin and Vimentin. Conclusions Our study revealed that MYOSLID expression was closely related to the p-EMT program in HNSCC, and it might be a new predictive biomarker for aggressive HNSCC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1254-4) contains supplementary material, which is available to authorized users.

BackgroundT-cell immunoglobulin mucin 3 (TIM3) is a negative immune checkpoint and plays a crucial part in tumor-induced immune suppression. However, the mechanism of TIM3 in regulating immunosuppression in head and neck squamous cell carcinoma (HNSCC) was still not quite clear.MethodsWe carried out the immunohistochemistry staining of HNSCC tissue microarrays. Through quantification of the histoscore, we performed the correlation analysis among the TIM3, Galectin-9, Foxp3, CD68 and CD163. The effects of TIM3 on regulatory T cells (Tregs) and macrophages were detected by utilizing the Tgfbr1/Pten 2cKO HNSCC mouse model. Flow cytometry were used to analysis the percent of Tregs, macrophages and IFN-γ.ResultsWe demonstrated the close association among TIM3/Galectin-9 pathway, regulatory T cell marker (Foxp3) and macrophage marker (CD68, CD163) in human HNSCC. In the transgenic HNSCC mouse model, blockade of TIM3 by the anti-TIM3 monoclonal antibody induced a reduction of CD4+CD25+Foxp3+ Tregs. Meanwhile, the population of TIM3+ Tregs was also decreased. However, the population of CD206+ macrophages was not significantly declined. The increased IFN-γ production on CD8+ T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors.ConclusionsThe present study demonstrated that TIM3 was associated with the immunosuppression in HNSCC. And targeting TIM3 can enhance anti-tumor immune response by decreasing Tregs in HNSCC.

Increased levels of inhibitors of the p53 tumor suppressor such as Mdm2 and Mdm4 drive tumor development and thus serve as targets for therapeutic intervention. Recently, digestive organ expansion factor (Diexf) has been identified as a novel inhibitor of p53 in zebrafish. Here, we address the potential role of Diexf as a regulator of the p53 pathway in mammals by generating Diexf knockout mice. We demonstrate that, similar to Mdm2 and Mdm4, homozygous deletion of Diexf is embryonic lethal. However, unlike in Mdm2 and Mdm4 mice, loss of p53 does not rescue this phenotype. Moreover, Diexf heterozygous animals are not sensitive to sub-lethal ionizing radiation. Thus, we conclude that Diexf is an essential developmental gene in the mouse, but is not a significant regulator of the p53 pathway during development or in response to ionizing radiation.