Neoadjuvant immunotherapy has the potential to enhance clinical outcomes by increasing anti-tumor immune responses in the presence of abundant tumor-derived antigen in an immune microenvironment that ...has not been exposed to previous therapy. The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. Although only 15-20% of patients benefit, immunotherapies have been approved and widely used for recurrent and metastatic HNSCC. These successes have led to checkpoint blockade therapies being testing in earlier treatment settings. Recent clinical trials of neoadjuvant immunotherapy show promising results and this methodology has the potential to change the treatment algorithm of HNSCC. This overview examines the treatment history of neoadjuvant approaches for HNSCC, and especially focuses on the recent topics of neoadjuvant immunotherapy for HNSCC.
Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen‐specific T cells. Head and neck squamous cell carcinoma (HNSCC) has a ...relatively high mutation burden across all cancer types, and cellular immunity to neoantigens likely plays a key role in HNSCC clinical outcomes. Immune checkpoint inhibitors (CPIs) have brought new treatment options and hopes to patients with recurrent and/or metastatic HNSCC. However, many patients do not benefit from CPI therapies, highlighting the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor‐associated antigens and tumor‐specific antigens, either as single agents or in combination with other therapies. Recent advances in next‐generation genomic sequencing technologies and computational algorithms have enabled efficient identification of somatic mutation‐derived neoantigens and are anticipated to facilitate the development of cancer vaccine strategies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of a cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.
Many patients with head and neck squamous cell carcinoma (HNSCC) do not benefit from checkpoint inhibitor therapies, which highlights the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor‐associated antigens and tumor‐specific antigens, either as single agents or in combination with other therapies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.
Cancer progression is facilitated by distinct mechanisms developed by cancer cells to avoid immune recognition and clearance. The clinical application of immune checkpoint blockade (ICB),
via
...monoclonal antibodies blocking PD-1/PD-L1 and CTLA4, has achieved promising durable therapeutic response in various cancer types, including recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). HNSCC represents a rational target of ICB treatment given its relatively high mutation burden and the presence of immune infiltrates. However, the limited response rates and recent negative clinical trials data identify an urgent need for new strategies to overcome immunotherapy resistance. Preclinical studies have revealed an important contribution of epigenetic regulators in the anti-tumor immune response. Multiple components of the tumor and host immune system interaction are under epigenetic regulation, including the cancer cells themselves, cytotoxic T lymphocytes, regulatory T lymphocytes, natural killer cells, and tumor-associated macrophages. Epigenetic targeting drugs such as DNA methyltransferase inhibitors, histone deacetylase, and methyltransferase inhibitors have demonstrated the potential to reverse immune suppression in various cancer models. The aim of this review is to summarize recent preclinical studies focused on investigating the function of epigenetic modulation in the host immune and cancer cell interface. We also provide a perspective on combining epigenetic modulation and immunotherapy in the management of HNSCC to improve outcomes—an area of great interest in future clinical studies.
Tumor cells can acquire a large amount of energy and structural components by reprogramming energy metabolism; moreover, metabolic profiles slightly differ according to cancer type. This study ...compared and assessed the metabolic profile of head and neck squamous cell carcinoma (HNSCC) and normal tissues, which were collected from patients without cancer.
Overall, 23 patients with HNSCC and 6 patients without cancer were included in the analysis. Metabolomic profiles were analyzed using capillary electrophoresis-mass spectrometry. Gene expression was evaluated using real-time reverse transcription-polymerase chain reaction.
Glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, and glutamine metabolism were upregulated in HNSCC tissues based on gene expression analysis. HNSCC could then have enhanced energy production and structural component. The levels of lactate, succinate, glutathione, 2-hydroxyglutarate, and S-adenosylmethionine, considered as oncometabolites, increased and these had accumulated in HNSCC tissues.
The level of metabolites and the expression of enzymes differ between HNSCC and normal tissues. Reprogramming metabolism in HNSCC provides an energy source as well as structural components, creating a system that offers rapid proliferation, progression, and is less likely to be eliminated.
Tendons are dense fibrous structures that attach muscles to bones. Healing of tendon injuries is a clinical challenge owing to poor regenerative potential and scarring. Here, we created reporter mice ...that express EGFP, driven by the promoter of the tendon-specific Scleraxis (Scx) transcription-factor gene; we then generated induced pluripotent stem cells (iPSCs) from these mice. Utilising these fluorescently labelled iPSCs, we developed a tenogenic differentiation protocol. The iPSC-derived EGFP-positive cells exhibited elevated expression of tendon-specific genes, including Scx, Mohawk, Tenomodulin, and Fibromodulin, indicating that they have tenocyte-like properties. Finally, we demonstrated that these cells promoted tendon regeneration in mice after transplantation into injured tendons reducing scar formation via paracrine effect. Our data demonstrate that the tenogenic differentiation protocol successfully provided functional cells from iPSCs. We propose that pluripotent stem cell-based therapy using this protocol will provide an effective therapeutic approach for tendon injuries.
T follicular helper (Tfh) cells provide signals to initiate and maintain the germinal center (GC) reaction and are crucial for the generation of robust, long-lived antibody responses, but how the GC ...microenvironment affects Tfh cells is not well understood. Here we develop an in vivo T cell-intrinsic CRISPR-knockout screen to evaluate Tfh and Th1 cells in an acute viral infection model to identify regulators of Tfh cells in their physiological setting. Using a screen of druggable-targets, alongside genetic, transcriptomic and cellular analyses, we identify a function of HIF-1α in suppressing mTORC1-mediated and Myc-related pathways, and provide evidence that VHL-mediated degradation of HIF-1α is required for Tfh development; an expanded in vivo CRISPR screen reveals multiple components of these pathways that regulate Tfh versus Th1 cells, including signaling molecules, cell-cycle regulators, nutrient transporters, metabolic enzymes and autophagy mediators. Collectively, our data serve as a resource for studying Tfh versus Th1 decisions, and implicate the VHL-HIF-1α axis in fine-tuning Tfh generation.
In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of ...primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells can differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors.
The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for ...precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.
Purpose
Pathogenic
MEFV
variants cause pyrin-associated autoinflammatory diseases (PAADs), which include familial Mediterranean fever (FMF), FMF-like disease, and pyrin-associated autoinflammation ...with neutrophilic dermatosis (PAAND). The diagnosis of PAADs is established by clinical phenotypic and genetic analyses. However, the pathogenicity of most
MEFV
variants remains controversial, as they have not been functionally evaluated. This study aimed to establish and validate a new functional assay to evaluate the pathogenicity of
MEFV
variants.
Methods
We transfected THP-1 monocytes with 32
MEFV
variants and analyzed their effects on cell death with or without stimulation with
Clostridium difficile
toxin A (TcdA) or UCN-01. These variants were classified using hierarchical cluster analysis. Macrophages were obtained from three healthy controls and two patients with a novel homozygous
MEFV
P257L
variant, for comparison of IL-1β secretion using a cell-based assay and a novel THP-1-based assay.
Results
Disease-associated
MEFV
variants induced variable degrees of spontaneous or TcdA/UCN-01-induced cell death in THP-1. Cell death was caspase-1 dependent and was accompanied by ASC speck formation and IL-1β secretion, indicating that pathogenic
MEFV
variants induced abnormal pyrin inflammasome activation and subsequent pyroptotic cell deaths in this assay. The
MEFV
variants (
n
= 32) exhibiting distinct response signatures were classified into 6 clusters, which showed a good correlation with the clinical phenotypes. Regarding the pathogenicity of
MEFV
P257L
variants, the results were consistent between the cell-based assay and the THP-1-based assay.
Conclusion
Our assay facilitates a rapid and comprehensive assessment of the pathogenicity of
MEFV
variants and contributes to a refined definition of PAAD subtypes.
Various liquid biopsy methods have been developed for the non-invasive and early detection of diseases. In particular, the detection of circulating tumor cells (CTCs) and cancer-associated ...fibroblasts (CAFs) in blood has been receiving a great deal of attention. We have been developing systems and materials to facilitate such liquid biopsies. In this study, we further developed glass filters (with various patterns of holes, pitches, and non-adhesive coating) that can capture CTCs, but not white blood cells. We optimized the glass filters to capture CTCs, and demonstrated that they could be used to detect CTCs from lung cancer patients. We also used the optimized glass filters for detecting CAFs. Additionally, we further developed a system for visualizing the captured cells on the glass filters. Finally, we demonstrated that we could directly culture the captured cells on the glass filters. Based on these results, our high-performance glass filters appear to be useful for capturing and culturing CTCs and CAFs for further examinations.
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