HMMR triggers immune evasion of hepatocellular carcinoma by inactivation of phagocyte killing.

Hepatocellular carcinoma (HCC) acquires an immunosuppressive microenvironment, leading to unbeneficial therapeutic outcomes. Hyaluronan-mediated motility receptor (HMMR) plays a crucial role in tumor progression. Here, we found that aberrant expression of HMMR could be a predictive biomarker for the immune suppressive microenvironment of HCC, but the mechanism remains unclear. We established an HMMR-/- liver cancer mouse model to elucidate the HMMR-mediated mechanism of the dysregulated "don't eat me" signal. HMMR knockout inhibited liver cancer growth and induced phagocytosis. HMMRhigh liver cancer cells escaped from phagocytosis via sustaining CD47 signaling. Patients with HMMRhighCD47high expression showed a worse prognosis than those with HMMRlowCD47low expression. HMMR formed a complex with FAK/SRC in the cytoplasm to activate NF-κB signaling, which could be independent of membrane interaction with CD44. Notably, targeting HMMR could enhance anti-PD-1 treatment efficiency by recruiting CD8+ T cells. Overall, our data revealed a regulatory mechanism of the "don't eat me" signal and knockdown of HMMR for enhancing anti-PD-1 treatment.

Nucleic acid-sensing-related gene signature in predicting prognosis and treatment efficiency of small cell lung cancer patients.

Introduction: Nucleic acid-sensing (NAS) pathways could induce innate and adaptive immune responses. However, rare evidence exhibited how the core genes of the NAS pathways affected the immune response and prognosis of small cell lung cancer (SCLC) patients. Methods: We conducted a comprehensive bioinformatic analysis based on the RNA profiles of 114 SCLC patients, including 79 from cBioPortal, 21 from GSE30219, and 14 from our sequencing data. The multiplex immunohistochemistry (mIHC) was used to characterize the role of NAS related genes in the tumor microenvironment (TME) of SCLC. Results: A prognostic model (7NAS risk model) was constructed based on 7 NAS-related genes which was demonstrated as an independent prognostic index. The low-risk group was identified to have a better prognosis and an immune-activated microenvironment in both the public datasets and our dataset. Intriguingly, mIHC data showed that CD45+ immune cells, CD8+ T lymphocytes, and CD68+ macrophages were prevalently enriched in low-risk SCLC patients and positively correlated with IRF1 expression. Additionally, Patients in the low-risk group might have superior responses to chemotherapy and immunotherapy. Conclusion: Conclusively, this study created a new risk model based on genes associated with NAS pathways which could predict the prognosis and response of treatment in patients with SCLC.

Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma.

Neoadjuvant chemoimmunotherapy (NACI) has shown promise in the treatment of resectable esophageal squamous cell carcinoma (ESCC). The microbiomes of patients can impact therapy response, and previous studies have demonstrated that intestinal microbiota influences cancer immunotherapy by activating gut immunity. Here, we investigated the effects of intratumoral microbiota on the response of patients with ESCC to NACI. Intratumoral microbiota signatures of ß-diversity were disparate and predicted the treatment efficiency of NACI. The enrichment of Streptococcus positively correlated with GrzB+ and CD8+ T-cell infiltration in tumor tissues. The abundance of Streptococcus could predict prolonged disease-free survival in ESCC. Single-cell RNA sequencing demonstrated that responders displayed a higher proportion of CD8+ effector memory T cells but a lower proportion of CD4+ regulatory T cells. Mice that underwent fecal microbial transplantation or intestinal colonization with Streptococcus from responders showed enrichment of Streptococcus in tumor tissues, elevated tumor-infiltrating CD8+ T cells, and a favorable response to anti-PD-1 treatment. Collectively, this study suggests that intratumoral Streptococcus signatures could predict NACI response and sheds light on the potential clinical utility of intratumoral microbiota for cancer immunotherapy. SIGNIFICANCE: Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.

YAP nuclear translocation facilitates radiation resistance in nasopharyngeal carcinoma cells.

OBJECTIVES: Investigate the role of the Hippo-YAP signaling pathway in radioresistant Nasopharyngeal Carcinoma (NPC). METHODS: Establishment of radioresistant CNE-1 cells (CNE-1-RR) by gradually increasing ionizing radiation (IR) doses, and identifying the apoptosis of CNE-1-RR by flow cytometry. We employed immunoblot and immunofluorescence staining to detect the expression of YAP in both CNE-1-RR and control group cells. Moreover, we validated the role of YAP in CNE-1-RR by inhibiting its nuclear translocation. RESULTS: In contrast to the control group, radioresistant NPC cells demonstrated significant YAP dephosphorylation and nuclear translocation. CNE-1-RR cells exhibited enhanced activation of γ-H2AX (Ser139) upon exposure to IR and greater recruitment of double-strand breaks (DSBs) repair-related proteins. Additionally, inhibiting YAP nuclear translocation in radioresistant CNE-1-RR cells significantly increased their sensitivity to radiotherapy. CONCLUSIONS: The present investigation has unveiled the intricate mechanisms and physiological roles of YAP in CNE-1-RR cells exhibiting resistance to IR. Based on our findings, it can be inferred that a combinational therapeutic strategy involving radiotherapy and inhibitors that impede the nuclear translocation of YAP holds promising potential for treating radioresistant NPC.

Mitochondria-targeting polydopamine-coated nanodrugs for effective photothermal- and chemo-synergistic therapies against lung cancer.

Targeting mitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance. Here, a mitochondria-targeting nanoparticle (TOS-PDA-PEG-TPP) was designed to precisely deliver polydopamine (PDA) as the photothermal agent and alpha-tocopherol succinate (α-TOS) as the chemotherapeutic drug to the mitochondria of the tumor cells, which inhibits the tumor growth through chemo- and photothermal- synergistic therapies. TOS-PDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled by α-TOS, followed by grafting PEG and triphenylphosphonium (TPP) on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells. In vitro studies showed that TOS-PDA-PEG-TPP could be efficiently internalized by tumor cells and accumulated at mitochondria, resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation. In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects. Conclusively, the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.

Blockading a new NSCLC immunosuppressive target by pluripotent autologous tumor vaccines magnifies sequential immunotherapy.

The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes (CTLs) allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy. Nanobiotechnology-engineered autologous tumor vaccines (ATVs) that were camouflaged by tumor cell membrane (TCM) were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells, consequently realizing the sequential immunotherapy. PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice. Immediately afterwards, phosphodiesterase-5 (PDE5) and programmed cell death 1 ligand 1 (PD-L1) dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC. Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor (i.e., l-arginine) exerted robust anti-tumor effects through increasing inducible nitric oxide synthase (iNOS) expression, blockading PDE5 pathway and activating systematic immune responses, which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models. The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.

Functional nanostructure-loaded three-dimensional graphene foam as a non-enzymatic electrochemical sensor for reagentless glucose detection.

Non-enzymatic and reagentless electrochemical sensors for convenient and sensitive detection of glucose are highly desirable for prevention, diagnosis and treatment of diabetes owing to their unique merits of simplicity and easy operation. Facile fabrication of a three-dimensional (3D) sensing interface with non-enzymatic recognition groups and an immobilized electrochemical probe remains challenge. Herein, a novel non-enzymatic electrochemical sensor was developed for the sensitive and reagentless detection of glucose by loading functional nanostructure on 3D graphene. Monolithic and macroporous 3D graphene (3DG) foam grown by chemical vapor deposition (CVD) served as the electrode scaffold. Prussian blue (PB) and gold nanoparticles (AuNPs) were first co-electrodeposited on 3DG (3DG/PB-AuNPs) as immobilized signal indicator and electron conductor. After a polydopamine (PDA) layer was introduced on 3DG/PB-AuNPs via facile self-polymerization of dopamine to stabilize internal PB probes and offer chemical reducibility, the second layer of AuNPs was in situ formed to assemble the recognition ligand, mercaptobenzoboric acid (MPBA). Owing to the high stability of PB and good affinity between MPBA and glucose, the non-enzymatic sensor was able to be used in reagentless detection of glucose with high selectivity, wide linear range (5 µM-65 µM) and low detection limit (1.5 µM). Furthermore, the sensor was used for the detection of glucose level in human serum samples.