Rationally Construction of Mn-Doped RuO2 Nanofibers for High-Activity and Stable Alkaline Ampere-Level Current Density Overall Water Splitting.

Nowadays, highly active and stable alkaline bifunctional electrocatalysts toward water electrolysis that can work at high current density (≥1000 mA cm-2) are urgently needed. Herein, Mn-doped RuO2 (MnxRu1-xO2) nanofibers (NFs) are constructed to achieve this object, presenting wonderful hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances with the overpotentials of only 269 and 461 mV at 1 A cm-2 in 1 m KOH solution, and remarkably stability under industrial demand with 1 A cm-2, significantly better than the benchmark Pt/C and commercial RuO2 electrocatalysts, respectively. More importantly, the assembled Mn0.05Ru0.95O2 NFs||Mn0.05Ru0.95O2 NFs electrolyzer toward overall water splitting reaches the current density of 10 mA cm-2 with a cell voltage of 1.52 V and also delivers an outstanding stability over 150 h of continuous operation, far surpassing commercial Pt/C||commercial RuO2, RuO2 NFs||RuO2 NFs and most previously reported exceptional electrolyzers. Theoretical calculations indicate that Mn-doping into RuO2 can significantly optimize the electronic structure and weaken the strength of O─H bond to achieve the near-zero hydrogen adsorption free energy (ΔGH*) value for HER, and can also effectively weaken the adsorption strength of intermediate O* at the relevant sites, achieving the higher OER catalytic activity, since the overlapping center of p-d orbitals is closer to the Fermi level.

Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer.

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Manganese drives ferroptosis of cancer cells via YAP/TAZ phase separation activated ACSL4 in OSCC.

OBJECTIVE: Ferroptosis has been defined as a novel form of regulated cell death characterized by iron-dependent lipid peroxidation. Manganese has been used to induce ferroptosis in cancer cells recently. This study aims to investigate whether manganese can induce ferroptosis in oral squamous cell carcinoma (OSCC) and the underlying biological mechanisms. MATERIALS AND METHODS: Cancer cells with or without manganese treatment were analyzed by RNA-sequencing to identify ferroptosis-related genes. Next, the activation of YAP/TAZ/ACSL4-ferroptosis signaling pathway was detected. Bioinformatic analysis and immunofluorescence assay were used to explore the phase separation of YAP/TAZ. Finally, specimens of OSCC patients were applied to analyze the clinical significance of YAP/TAZ/ACSL4. RESULTS: RNA-sequencing analysis showed the ferroptosis-related genes and YAP/TAZ were upregulated after manganese treatment. The results of immunofluorescence, ELISA, western blotting, etc. further confirmed that manganese-induced ferroptosis depends on YAP/TAZ/ACSL4 signaling pathway. Moreover, the activation of ACSL4 was achieved by YAP/TAZ phase separation. The survival analysis in OSCC specimen suggested that the higher level of YAP/TAZ-ACSL4 axis expression indicates longer survival. CONCLUSIONS: Manganese induces YAP/TAZ phase separation and subsequent ACSL4 activation via YAP/TAZ nuclear translocation, which facilitates ferroptosis of OSCC. Then YAP/TAZ-ACSL4 axis can be used as a potential prognostic predictor of OSCC patients.

STAT3 promotes differentiation of monocytes to MDSCs via CD39/CD73-adenosine signal pathway in oral squamous cell carcinoma.

Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.

Ferroptosis promotes anti-tumor immune response by inducing immunogenic exposure in HNSCC.

Accumulated evidence indicates that immune cell populations play pivotal roles in the process of tumor initiation, progression, recurrence, metastasis, and immune escape. Ferroptosis is a form of regulating cell death in the nexus between metabolism, redox biology, and human health. Ferroptosis is considered as a vital important event in HNSCC, but the underling mechanism of regulating immune cell populations remains poorly understood. Our tissue microarray study showed that patients with high expression of GPX4 were related to poor survival. Moreover, the expression of GPX4 has been negatively associated with immunogenic cell death-related protein calreticulin in HNSCC tissue cohort. Further, RSL3 was used to induce ferroptosis in HNSCC xenograft of C3H/He mouse. We found that the occurrence of ferroptosis had significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (M2 TAMs) in tumor microenvironment. Meanwhile, the tumor-infiltrating CD4+ and CD8+ T cells were increased. And the calreticulin and HMGB1 may be potential candidate proteins improving the immunosuppressive tumor microenvironment. Taken together, our project suggests that ferroptosis can promote anti-tumor immune response by reversing immunosuppressive microenvironment, indicating that ferroptosis inducer is a promising therapeutic strategy in HNSCC.

Advanced materials and technologies for oral diseases.

Oral disease, as a class of diseases with very high morbidity, brings great physical and mental damage to people worldwide. The increasing burden and strain on individuals and society make oral diseases an urgent global health problem. Since the treatment of almost all oral diseases relies on materials, the rapid development of advanced materials and technologies has also promoted innovations in the treatment methods and strategies of oral diseases. In this review, we systematically summarized the application strategies in advanced materials and technologies for oral diseases according to the etiology of the diseases and the comparison of new and old materials. Finally, the challenges and directions of future development for advanced materials and technologies in the treatment of oral diseases were refined. This review will guide the fundamental research and clinical translation of oral diseases for practitioners of oral medicine.

Theoretical Investigation of HER and OER Electrocatalysts Based on the 2D R-graphyne Completely Composed of Anti-Aromatic Carbon Rings.

Based on the DFT calculations, two-dimensional (2D) R-graphyne has been demonstrated to have high stability and good conductivity, which can be conducive to the relevant electrocatalytic activity of the material. Different from the poor graphene, R-graphyne, which is completely composed of anti-aromatic structural units, can exhibit certain HER catalytic activity. In addition, doping the TM atoms in Group VIIIB can be considered an effective strategy to enhance the HER catalytic activity of R-graphyne. Particularly, Fe@R-graphyne, Os@R-graphyne, Rh@R-graphyne and Ir@R-graphyne can exhibit higher HER catalytic activities due to the formation of more active sites. Usually, the shorter the distance between the TM and C atoms is, the better the HER activity of the C-site is. Furthermore, doping Ni and Rh atoms of Group VIIIB can significantly improve the OER catalytic performance of R-graphyne. It can be found that ΔGO* can be used as a good descriptor for the OER activities of TM@R-graphyne systems. Both Rh@R-graphyne and Ni@R-graphyne systems can exhibit bifunctional electrocatalytic activities for HER/OER. In addition, all the relevant catalytic mechanisms are analyzed in detail. This work not only provides nonprecious and highly efficient HER/OER electrocatalysts, but also provides new ideas for the design of carbon-based electrocatalysts.

Realizing Efficient Catalytic Performance and High Selectivity for Oxygen Reduction Reaction on a 2D Ni2SbTe2 Monolayer.

One of the immediate challenges for the large-scale commercialization of hydrogen-based fuel cells is to develop cost-effective electrocatalysts to enable cathodic oxygen reduction reaction (ORR). Herein, we focus on the potential of the two-dimensional (2D) ternary chalcogenide Ni2SbTe2 monolayer as a high-performance electrocatalyst for the ORR using density function theory. Our computed results reveal that there are an obvious hybridization and electron transfer between the O 2p and Te 5p orbitals, which can activate the adsorbed oxygen and trigger the whole ORR process, with an overpotential as low as 0.33 V. In addition, the adsorption capacity of the monolayer surface for oxygen molecules can be effectively enhanced by doping with Fe or Co atoms. The Ni2SbTe2 monolayers doped with Fe or Co atoms not only maintain their original excellent ORR catalytic activity but also improve selectivity toward the four-electron (4e) reduction pathway. We highly anticipate that this work can provide excellent candidates and new ideas for designing low-cost and high-performance ORR catalysts to replace noble metal Pt-based catalysts in fuel cells.

CD24 blockade promotes anti-tumor immunity in oral squamous cell carcinoma.

OBJECTIVES: Our study elucidates the prognostic role of cluster of differentiation (CD) 24 expression in oral squamous cell carcinoma (OSCC) and determines whether targeting CD24 enhances the anti-tumor immune response by inhibiting tumor-associated macrophages (TAMs). MATERIALS AND METHODS: The expression of CD24 and CD68 was analyzed immunohistochemically via tissue microarrays constructed using 56 cohorts of patients with OSCC and 20 control specimens. Further, CD24 was inhibited in an allograft squamous cell carcinoma (SCC) related mouse model with CD24mAb to determine the tumor volume and weight. Changes in immune cells such as TAMs and T cells in the tumor microenvironment (TME) were analyzed by Flow cytometry. The expression of CD4, CD8, and Ki67 was analyzed via immunohistochemistry. The inhibition of CD24 was confirmed by Western blot and immunohistochemistry. RESULTS: CD24 was overexpressed in OSCC. High expression of CD24 indicated poor survival in patients with OSCC (p = 0.0334). CD24 expression was significantly correlated with CD68 (p = 0.0424). The inhibition of CD24 delayed tumor growth in vivo. A decrease in TAMs number and an increase in T cell number were confirmed, while the ability of tumor proliferation was impaired. CONCLUSION: Targeting CD24 could enhance anti-tumor immune response by inhibiting TAMs.

Theoretical Study on the High HER/OER Electrocatalytic Activities of 2D GeSi, SnSi, and SnGe Monolayers and Further Improvement by Imposing Biaxial Strain or Doping Heteroatoms.

Under the DFT calculations, two-dimensional (2D) GeSi, SnSi, and SnGe monolayers, considered as the structural analogues of famous graphene, are confirmed to be dynamically, mechanically and thermodynamically stable, and all of them can also possess good conductivity. Furthermore, we systematically investigate their electrocatalytic activities in overall water splitting. The SnSi monolayer can show good HER catalytic activity, while the SnGe monolayer can display remarkable OER catalytic activity. In particular, the GeSi monolayer can even exhibit excellent bifunctional HER/OER electrocatalytic activities. In addition, applying the biaxial strain or doping heteroatoms (especially P atom) can be regarded as the effective strategies to further improve the HER activities of these three 2D monolayers. The doped GeSi and SnSi systems can usually exhibit higher HER activity than the doped SnGe systems. The correlative catalytic mechanisms are also analyzed. This work could open up a new avenue for the development of non-noble-metal-based HER/OER electrocatalysts.

Embedding Group VIII Elements into a 2D Rigid pc-C3N2 Monolayer to Achieve Single-Atom Catalysts with Excellent OER Activity: A DFT Theoretical Study.

Under DFT calculations, a systematic investigation is carried out to explore the structures and oxygen evolution reaction (OER) catalytic activities of a series of 2D single-atom catalyst (SAC) systems, which are constructed by doping the transition metal (TM) atoms in group VIII into the cavities of rigid phthalocyanine carbide (pc-C3N2). We can find that when Co, Rh, Ir and Ru atoms are doped in the small or large cavities of a pc-C3N2 monolayer, they can be used as high-activity centers of OER. All these four new TM@C3N2 nanostructures can exhibit very low overpotential values in the range of 0.33~0.48 V, even smaller than the state-of-the-art IrO2 (0.56 V), which indicates considerably high OER catalytic activity. In particular, the Rh@C3N2 system can show the best OER performance, given that doped Rh atoms can uniformly serve as high-OER-active centers, regardless of the size of cavity. In addition, a detailed mechanism analysis was carried out. It is found that in these doped pc-C3N2 systems, the number of outer electrons, the periodic number of doped TM atoms and the size of the embedded cavity can be considered the key factors affecting the OER catalytic activity, and excellent OER catalytic performance can be achieved through their effective cooperation. These fascinating findings can be advantageous for realizing low-cost and high-performance SAC catalysts for OER in the near future.

3D Hydrazone-Functionalized Covalent Organic Frameworks as pH-Triggered Rotary Switches.

The property expansion of 3D functionalized covalent organic frameworks (COFs) is important for developing their potential applications. Herein, the first case of 3D hydrazone-decorated COFs as pH-triggered molecular switches is reported, and their application in the stimuli-responsive drug delivery system is explored. These functionalized COFs with hydrazone groups on the channel walls are obtained via a multi-component bottom-up synthesis strategy. They exhibit a reversible E/Z isomerization at various pH values, confirmed by UV-vis absorption spectroscopy and proton conduction. Remarkably, after loading cytarabine (Ara-C) as a model drug molecule, these pH-responsive COFs show an excellent and intelligent sustained-release effect with an almost fourfold increase in the Ara-C release at pH = 4.8 than at pH = 7.4, which will effectively improve drug-targeting. Thus, these results open a way toward designing 3D stimuli-responsive functionalized COF materials and promote their potential application as drug carriers in the field of disease treatment.

Genetically Programmable Fusion Cellular Vesicles for Cancer Immunotherapy.

Herein, we report that genetically programmable fusion cellular vesicles (Fus-CVs) displaying high-affinity SIRPα variants and PD-1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual-blockade of CD47 and PD-L1 with Fus-CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T-cell immunity. Moreover, the bispecific targeting design of Fus-CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus-CVs significantly improve overall survival of model animals by inhibiting post-surgery tumor recurrence and metastasis. The Fus-CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus-CVs an attractive platform for multi-targeting immune checkpoint blockade therapy.

Embedding tetrahedral 3d transition metal TM4 clusters into the cavity of two-dimensional graphdiyne to construct highly efficient and nonprecious electrocatalysts for hydrogen evolution reaction.

On the basis of density functional theory (DFT) calculations, we have systematically investigated the structures and hydrogen evolution reaction (HER) catalytic activities for a series of new composite systems TM4@GDY (TM = Sc, Ti, Mn, Fe, Co, Ni and Cu), which are constructed by embedding tetrahedral 3d transition metal TM4 clusters in the in-plane cavity of two-dimensional (2D) π-conjugated graphdiyne (GDY). Our computed results reveal that compared with the constituent subunits, namely the sole TM4 cluster and GDY, all these composite TM4@GDY nanostructures can uniformly exhibit considerably high HER catalytic activity over a wide range of hydrogen coverage, and especially the Fe4@GDY and Co4@GDY systems can possess higher HER activity, in view of their higher number of active sites. The high HER catalytic activity for TM4@GDY can be mainly due to the occurrence of obvious electron transfer from TM4 cluster to GDY, significantly activating the correlative C and TM atoms. Moreover, all these composite TM4@GDY systems can also exhibit high structural stability and good conductivity. Therefore, all of them can be considered as a new kind of promising HER catalyst, and this study can provide new strategies for designing low-cost and high-performance 2D carbon-based electrocatalysts.

Theoretical predication of the high hydrogen evolution catalytic activity for the cubic and tetragonal SnP systems.

By means of density functional theory (DFT) calculations, we have systematically investigated the structures and hydrogen evolution reaction (HER) catalytic activities for the cubic and tetragonal SnP systems, both of which can be viewed as the stacking of SnP layers possessing structural features similar to the famous phosphorene. It is revealed that the (111) and (200) facets are the possible exposed surfaces of the cubic structure, while the possible exposed surfaces of the tetragonal structure are (101), (101[combining macron]), (110), (002) and (002[combining macron]) facets. The computed surface energies reveal that the P-terminated (111) surface and the (200) surface of the cubic SnP system as well as the P-terminated (101) and (101[combining macron]) surfaces and the (110) surface of the tetragonal SnP system can be considered as the more stable surfaces, in view of more favorable surface energy. The computed free energy values of H* (ΔGH*) show that all these stable surfaces can possess considerably high HER catalytic activity over a wide range of hydrogen coverage. It is found that the top sites over P atoms can serve as the most active sites on these surfaces, and the tetragonal structure can even exhibit a higher HER activity than the cubic structure. Moreover, the correlative catalytic mechanisms have been analyzed in detail. Coupled with the metallic conductivity, two kinds of bulk SnP systems can be very promising candidates as a high-performance and low-cost HER electrocatalyst. All these fascinating findings can be beneficial for promoting the application of excellent SnP-based materials in catalyzing the water splitting process.

Theoretical design of a series of 2D TM-C3N4 and TM-C3N4@graphene (TM = V, Nb and Ta) nanostructures with highly efficient catalytic activity for the hydrogen evolution reaction.

Inspired by the fascinating result that NbN-related species can possess a similar electronic structure to noble metal atoms (e.g. Pt), in this work we have proposed for the first time a new strategy, through embedding the transition metal (TM) Nb atom in the in-plane cavity of g-C3N4, for constructing the nonprecious Nb-C3N4 configuration comprising the NbN unit exhibiting noble-metal-like characteristics. Our computed results reveal that embedding Nb can significantly improve the catalytic activity for the hydrogen evolution reaction (HER) of g-C3N4, and even that the formed Nb-C3N4 can exhibit a considerably high HER catalytic activity over a wide range of hydrogen coverage. Similarly, such a high HER activity can also be observed in the analogous V- or Ta-doped g-C3N4 systems. Furthermore, a series of new hybrid systems TM-C3N4@G (TM = V, Nb or Ta) is constructed by coupling the single-layered TM-C3N4 with graphene, and all of them can also possess a considerably high HER catalytic activity over a wide range of hydrogen coverage. Moreover, all these composite TM-C3N4 and TM-C3N4@G systems possess high structural stability and metallic conductivity. Thus, all of them can be viewed as a new class of promising HER catalysts, and this work can also provide new strategies for designing low-cost and high-performance electrocatalysts.

Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma.

The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT) is associated with metastasis formation, generation and maintenance of cancer stem cells (CSCs). However, the regulatory mechanisms of CSCs have not been clarified. This study aims to investigate the role of TNF receptor-associated factor 6 (TRAF6) on EMT and CSC regulation in squamous cell carcinoma of head and neck (SCCHN). We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN. In addition, elevated TRAF6 expression was observed in several HNSCC cell lines, and wound healing and transwell assay results showed that TRAF6 knockdown inhibited the migration and invasion ability of the SCCHN cells. Moreover, the expression of Vimentin, Slug and N-cadherin was down-regulated and that of E-cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF-ß1) and CAL27 similar to mesenchymal cells formed after TGF-ß1 induction. In addition, the expression levels of CD44, ALDH1, KLF4 and SOX2 were inhibited after TRAF6 knockdown, and the anchor-dependent colony formation number and sphere number were remarkably reduced. Flow cytometry showed TRAF6 knockdown reduced ALDH1-positive cancer stem cells. We also demonstrated that TRAF6 is closely associated with EMT process and cancer stem cells using a Tgfbr1/Pten 2cKO mice SCCHN model and human SCCHN tissue microarray. Our findings indicate that TRAF6 plays a role in EMT phenotypes, the generation and maintenance of CSCs in SCCHN, suggesting that TRAF6 is a potential therapeutic target for SCCHN.

Specific blockade CD73 alters the "exhausted" phenotype of T cells in head and neck squamous cell carcinoma.

The adenosine-induced immunosuppression hampers the immune response toward tumor cells and facilitates the tumor cells to evade immunosurveillance. CD73, an ecto-5-nucleotidase, is the ectoenzyme dephosphorylating extracellular AMP to adenosine. Here, using immunocompetent transgenic head and neck squamous cell carcinoma (HNSCC) mouse model, immune profiling showed high expression of CD73 on CD4+ and CD8+ T cells was associated with an "exhausted" phenotype. Further, treatment with anti-CD73 monoclonal antibody (mAb) significantly blunted the tumor growth in the mouse model, and the blockade of CD73 reversed the "exhausted" phenotype of CD4+ and CD8+ T cells through downregulation of total expression of PD-1 and CTLA-4 on T cells. Whereas the population of CD4+ CD73hi /CD8+ CD73hi T cells expressed higher CTLA-4 and PD-1 as compared to untreated controls. In addition, the human tissue microarrays showed the expression of CD73 is upregulated on tumor infiltrating immune cells in patients with primary HNSCC. Moreover, CD73 expression is an independent prognostic factor for poor outcome in our cohort of HNSCC patients. Altogether, these findings highlight the immunoregulatory role of CD73 in the development of HNSCC and we propose that CD73 may prove to be a promising immunotherapeutic target for the treatment of HNSCC.

γ-Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma.

Immune evasion is a hallmark feature of cancer, and it plays an important role in tumour initiation and progression. In addition, tumour immune evasion severely hampers the desired antitumour effect in multiple cancers. In this study, we aimed to investigate the role of the Notch pathway in immune evasion in the head and neck squamous cell carcinoma (HNSCC) microenvironment. We first demonstrated that Notch1 signaling was activated in a Tgfbr1/Pten-knockout HNSCC mouse model. Notch signaling inhibition using a γ-secretase inhibitor (GSI-IX, DAPT) decreased tumour burden in the mouse model after prophylactic treatment. In addition, flow cytometry analysis indicated that Notch signaling inhibition reduced the sub-population of myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T cells (Tregs), as well as immune checkpoint molecules (PD1, CTLA4, TIM3 and LAG3), in the circulation and in the tumour. Immunohistochemistry (IHC) of human HNSCC tissues demonstrated that elevation of the Notch1 downstream target HES1 was correlated with MDSC, TAM and Treg markers and with immune checkpoint molecules. These results suggest that modulating the Notch signaling pathway may decrease MDSCs, TAMs, Tregs and immune checkpoint molecules in HNSCC.