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Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors.

Tumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients. Tumour-infiltrating lymphocytes play a crucial role in neuroblastoma, but their relationship to other immune cells is poorly understood. Here the authors identify the cellular and gene signatures of intratumoural dendritic cells and natural killer cells that predict the clinical outcome of neuroblastoma.

Despite the significant clinical advances with the use of immune checkpoint inhibitors (ICIs) in a wide range of cancer patients, response rates to the therapy are variable and do not always result in long-term tumor regression. The development of ICI-resistant disease is one of the pressing issue in clinical oncology, and the identification of new targets and combination therapies is a crucial point to improve response rates and duration. Antigen processing and presentation (APP) pathway is a key element for an efficient response to ICI therapy. Indeed, malignancies that do not express tumor antigens are typically poor infiltrated by T cells and unresponsive to ICIs. Therefore, improving tumor immunogenicity potentially increases the success rate of ICI therapy. In this review, we provide an overview of the key elements of the APP machinery that can be exploited to enhance tumor immunogenicity and increase the efficacy of ICI-based immunotherapy.

While correlations between postural stability deficits and schizophrenia are well documented, information on dynamic motor alterations in schizophrenia are still scarce, and no data on their onset are available yet. Therefore, the aim of this study was i) to measure gait pattern(s) in patients with schizophrenia; ii) to identify posture and gait alterations which could potentially be used as a predictive clinical tool of the onset of the disorder. Body composition, posture and gait parameters were assessed in a group of 30 patients with schizophrenia and compared to 25 healthy subjects. Sway area was significantly higher in the schizophrenia group compared to controls regardless of whether the participants were in eyes open or eyes closed condition. Gait cadence and speed were significantly lower in patients with schizophrenia, while stride length was similar. We concluded that the combination of an increased sway area (independent from eye closure) and a gait cadence reduction—in the presence of normal gait speed and stride length—might be considered peculiar postural and gait profile characteristic of early schizophrenia.

NK cell-based immunotherapy of solid tumors has been shown to be increasingly successful, but much effort is still needed to optimize its efficacy. This study explores the effects of treatment with low, non-toxic doses of IFN-γ and TNF-α on the susceptibility of breast cancer (BC) cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) cultured in 2D and 3D as spheroids, to NK cell-mediated antitumor function. We evaluated the expression of (i) ligands for NK cell-activating receptors on BC cells, (ii) death and adhesion molecules on BC cells, and (iii) the expression of NK cell-receptors on NK cells infiltrating BC spheroids. Cytokine treatment significantly increased the expression of FAS, TRAIL-R2, and ICAM-1 in all BC cell lines, enhancing NK cell-mediated apoptosis and promoting NK cell-tumor cell conjugate formation. Differently, the expression of ligands for activating receptors remained essentially unchanged. In BC spheroids, the treatment with IFN-γ and TNF-α enhanced NK-cell infiltration, with increased expression of activating receptors (NKG2D, DNAM-1, NKp30, and NKp46) on infiltrating NK cells. However, regardless of treatment, markers of NK cell exhaustion, such as PD-1 and CTLA-4, were also upregulated, the latter especially in triple-negative BC (TNBC) MDA-MB-231 spheroids, thus suggesting an exhausted phenotype of NK cells infiltrating spheroids despite activation. Cytokine treatment resulted in a significant NK cell-mediated reduction in spheroid size, accompanied by an increased apoptotic state, with effects more pronounced in MCF-7 than in MDA-MB-231 spheroids. These results indicate that, although the treatment with IFN-γ and TNF-α improves NK cell-mediated tumor interaction and apoptosis, its therapeutic efficacy may be dependent on the BC subtype, with TNBC spheroids showing greater resistance. These findings highlight the importance of the tumor microenvironment (TME) in shaping NK cell responses and suggest that combining IFN-γ and TNF-α treatments with NK-cell-based immunotherapeutic strategies may improve treatment outcomes, particularly for more aggressive BC subtypes.

Natural Killer (NK) cells play a key role in both innate and adaptive immune responses against viruses and tumor cells. Their function relies on the dynamic balance between activating and inhibitory signals, which are mediated by receptors that bind ligands expressed on target cells. While much is known about the function and expression patterns of NK cell activating receptors (NKARs), many of their ligands remain unidentified. K562 cells were transduced with a shRNA library targeting 15,000 genes and co-cultured with NK cells from healthy donors. Surviving clones were tested in cytotoxicity and degranulation assays. PLAC1 was cloned from JEG3 cells in a lentiviral vector and transfected in K562 cells. PLAC1-related gene expression and survival data were obtained from the TCGA database and analyzed using R. PLAC1 and DSG2 expression in healthy tissues and NK cells was obtained from the HPA database and a GEO dataset. We identified ten candidate genes whose downregulation in K562 cells decreased NK cell-mediated cytotoxicity to levels comparable to silencing the MICA gene. The most promising candidates were functionally validated through single-target gene silencing and overexpression. Among them, the placenta-specific 1 ( ) gene stood out, as its inhibition conferred the greatest protection to target cells from NK cell lysis, while overexpression of PLAC1 significantly increased NK cell degranulation. Importantly, PLAC1 was found to interact with NKAR fusion proteins, including NKG2D, DNAM1 NKp44 and NKp30, suggesting its potential involvement in NK cell function. PLAC1 is typically silent in normal tissues, with the exception of placental trophoblasts and testicular germ cells, but is markedly overexpressed in a wide range of tumors. Notably, its prognostic significance appears to be tumor-type specific, associating with either favorable or poor outcomes depending on the cancer context. Our study identifies PLAC1 as a novel potential ligand for NKARs, suggesting it could be a valuable target for pharmacological strategies aimed at enhancing NK cell recognition. This finding holds promise for improving the efficacy of NK cell-based immunotherapies and advancing their clinical application.

Background Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response. Methods 975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed. Results We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8 + T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8 + T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8 + T cells and NK cells. Conclusions Combined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.

The prognosis for patients with head and neck cancer (HNC) is usually poor, highlighting the need for new therapeutic strategies. To this end, this study aims to evaluate the antitumor efficacy of a combined treatment with low doses of different molecular targeted drugs, i.e. Y15, a FAK inhibitor, Afatinib (AFA) an ErbB inhibitor and TP-0903, an Axl inhibitor, on HNC. Human cell lines from salivary gland, tongue and pharynx HNC, cultured in 2D and 3D (spheroids) conditions, were used to evaluate the antitumor effects of Y15, AFA and TP-0903, alone or in combination. Cell survival, death and migration were evaluated. Western blotting and immunofluorescence analysis were performed to investigate the expression and activation of proteins involved in signal transduction and epithelial to mesenchymal transition. The combined treatment with low doses of Y15, AFA and TP-0903, was more effective than the individual and dual drug treatments in reducing survival, increasing cell death and reducing migration of HNC cells. The three inhibitors in combination had a synergistic effect in reducing survival of HNC cell lines in both 2D and 3D conditions. Moreover, as compared to the individual inhibitors and their pairwise combinations, the triple drug combination was the only able to simultaneously downregulate Axl, FAK, and N-cadherin while upregulating E-cadherin expression levels. The results reported herein provide compelling preliminary evidence supporting the combined use of Y15, AFA and TP-0903 as a novel therapeutic strategy for HNCs. Clinical trial number Not applicable.

Background Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and low neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides before loading on MHC class I molecules. Inhibition of ERAP1 results in the generation of new antigens able of inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinatorial strategy based on genetic inhibition of ERAP1 and administration of the HDAC inhibitor (HDACi) entinostat that increase the immunogenicity of NB, making it responsive to PD-1 therapy. Methods CRISPR/Cas9-mediated gene editing was used to knockout (KO) the ERAP1 gene in 9464D NB cells derived from spontaneous tumors of TH-MYCN transgenic mice. The expression of MHC class I and PD-L1 was evaluated by flow cytometry (FC). The immunopeptidome of these cells was studied by mass spectrometry. Cocultures of splenocytes derived from 9464D bearing mice and tumor cells allowed the assessment of the effect of ERAP1 inhibition on the secretion of inflammatory cytokines and activation and migration of immune cells towards ERAP1 KO cells by FC. Tumor cell killing was evaluated by Caspase 3/7 assay and flow cytometry analysis. The effect of ERAP1 inhibition on the immune content of tumors was analyzed by FC, immunohistochemistry and multiple immunofluorescence. Results We found that inhibition of ERAP1 makes 9464D cells more susceptible to immune cell-mediated killing by increasing both the recall and activation of CD4 + and CD8 + T cells and NK cells. Treatment with entinostat induces the expression of MHC class I and PD-L1 molecules in 9464D both in vitro and in vivo. This results in pronounced changes in the immunopeptidome induced by ERAP1 inhibition, but also restrains the growth of ERAP1 KO tumors in vivo by remodelling the tumor-infiltrating T-cell compartment. Interestingly, the absence of ERAP1 in combination with entinostat and PD-1 blockade overcomes resistance to PD-1 immunotherapy and increases host survival. Conclusions These findings demonstrate that ERAP1 inhibition combined with HDACi entinostat treatment and PD-1 blockade remodels the immune landscape of a non-immunogenic tumor such as NB, making it responsive to checkpoint immunotherapy.

The field of speech emotion recognition (SER) encompasses a wide variety of approaches, with artificial intelligence technologies providing improvements in recent years. In the domain of mental health, the links between individuals' emotional states and pathological diagnoses are of particular interest. This study aimed to investigate the performance of tools combining SER and artificial intelligence approaches with a view to their use within clinical contexts and to determine the extent to which SER technologies have already been applied within clinical contexts. The review includes studies applied to speech (audio) signals for a select set of pathologies or disorders and only includes those studies that evaluate diagnostic performance using machine learning performance metrics or statistical correlation measures. The PubMed, IEEE Xplore, arXiv, and ScienceDirect databases were queried as recently as February 2025. The Quality Assessment of Diagnostic Accuracy Studies tool was used to measure the risk of bias. A total of 14 articles were included in the final review. The included papers addressed suicide risk (3/14, 21%), depression (8/14, 57%), and psychotic disorders (3/14, 21%). SER technologies are mostly used indirectly in mental health research and in a wide variety of ways, including different architectures, datasets, and pathologies. This diversity makes a direct assessment of the technology challenging. Nonetheless, promising results are obtained in various studies that attempt to diagnose patients based on either indirect or direct results from SER models. These results highlight the potential for this technology to be used within a clinical setting. Future work should focus on how clinicians can use these technologies collaboratively. PROSPERO CRD420251006669; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251006669.