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Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING . The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206 + myeloid cells and reduced effector CD8 + T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

Cancer stem cells (CSC) are a subpopulation of cancer cells that exhibit properties of self-renewal and differentiation and have been implicated in metastasis and treatment failures. There is mounting evidence that carcinogen-initiated mucosal epithelial stem cells acquire the CSC phenotype following exposure to environmental or infectious mutagens and are responsible for promoting the malignant transformation of premalignant (dysplastic) epithelium. CSC further contribute to the progression of dysplasia by activating signaling pathways through crosstalk with various cell populations in the tumor microenvironment. Two cell types, tumor-associated macrophages (TAM) and vascular endothelial cells (EC) nurture CSC development, support CSC stemness, and contribute to tumor progression. Despite mounting evidence implicating CSC in the initiation and progression of dysplastic oral epithelium to squamous cell carcinoma (SCC), the molecular mechanisms underlying these synergistic biological processes remain unclear. This review will examine the mechanisms that underlie the transformation of normal epithelial stem cells into CSC and the mechanistic link between CSC, TAM, and EC in the growth and the malignant conversation of dysplastic oral epithelium.

Cancer stem cells (CSC) are endowed with multipotency, self-renewal and unique tumorigenic potential. They have been identified as cells with high activity of aldehyde dehydrogenase (ALDH) and high expression of CD44 in head and neck squamous cell carcinoma (HNSCC). The objective of this work is to understand whether salivary gland adenoid cystic carcinoma contain CSCs and whether they exhibit a unique tumorigenic activity in this cancer. We used flow cytometry, salisphere and western blot assays with 3 human ACC cell lines (UM-HACC-2A, UM-HACC-14, UM-HACC-6) to characterize the impact of ALDH activity and CD44 expression. results were verified by orthotopic injection of cells retrieved from a patient-derived xenograft (PDX) model of ACC (UM-PDX-HACC-14) in the submandibular gland of SCID mice. Primary tumor and metastatic spread were evaluated by 2 pathologists blinded for experimental conditions. The fraction of ALDH CD44 cells in UM-HACC-2A, UM-HACC-14 and UM-HACC-6 ranged from 3% to 8%. ALDH CD44 cells formed more salispheres and expressed higher levels of stem cell markers (e.g., Notch2, Bmi-1) compared to control ALDH CD44 cells. ALDH CD44 cells sorted from the ACC PDX tumors were more tumorigenic upon orthotopic transplantation into submandibular salivary glands and generated more lung metastases than control ACC cells. Strong ALDH1A1 staining was observed in the majority of salivary gland tumors and lung metastases generated by transplantation of ALDH CD44 cells. We conclude that salivary gland adenoid cystic carcinoma contain a small population of uniquely tumorigenic cells characterized by high ALDH activity and expression.

For decades, the link between poor oral hygiene and the increased prevalence of oral cancer has been suggested. Most recently, emerging evidence has suggested that chronic inflammatory diseases from the oral cavity (e.g., periodontal disease), to some extent, play a role in the development of oral squamous cell carcinoma (OSCC). The present study aimed to explore the direct impact of biofilm-induced periodontitis in the carcinogenesis process using a tobacco surrogate animal model for oral cancer. A total of 42 Wistar rats were distributed into four experimental groups: Control group, periodontitis (Perio) group, 4-nitroquinoline 1-oxide (4-NQO) group and 4NQO/Perio group. Periodontitis was stimulated by placing a ligature subgingivally, while oral carcinogenesis was induced by systemic administration of 4NQO in the drinking water for 20 weeks. It was observed that the Perio, 4NQO and 4NQO/Perio groups presented with significantly higher alveolar bone loss compared with that in the control group. Furthermore, all groups receiving 4NQO developed lesions on the dorsal surface of the tongue; however, the 4NQO/Perio group presented larger lesions compared with the 4NQO group. There was also a modest overall increase in the number of epithelial dysplasia and OSCC lesions in the 4NQO/Perio group. Notably, abnormal focal activation of cellular differentiation (cytokeratin 10-positive cells) that extended near the basal cell layer of the mucosa was observed in rats receiving 4NQO alone, but was absent in rats receiving 4NQO and presenting with periodontal disease. Altogether, the presence of periodontitis combined with 4NQO administration augmented tumor size in the current rat model and tampered with the protective mechanisms of the cellular differentiation of epithelial cells.

Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC), but clinical trials are lacking. This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The co-primary endpoints are determination of dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy +/- carboplatin. Secondary endpoints include safety, survival, and RR by tumor histology. After enrollment of 4 patients to combination therapy, the trial was modified to a single arm study of alrizomadlin monotherapy due to excess toxicity. 1 DLT was seen in the combination arm, all patients had ≥ G3 treatment related adverse events (TRAE). 37 patients were enrolled to alrizomadlin monotherapy. 3 DLTs were encountered, 67% of patients had ≥ G3 TRAE. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC. Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC). Here the authors present a phase I clinical trial reporting tolerability and efficacy preliminary data for the MDM2 inhibitor alrizomadlin (APG-115) in patients with TP53 wild type salivary gland cancers, especially adenoid cystic carcinoma.

Introduction: The COVID-19 pandemic has significantly impacted all public life and the global economy. Since its discovery, the disease has spread rapidly, which led to an unprecedented public health crisis and the adoption of extreme measures to limit community and hospital spread. As a result of a confluence of extraordinary circumstances caused by this pandemic, the doctrines of treatment for patients with head and neck carcinoma had to be reanalyzed, guaranteeing the well-being of both patients and health professionals as well as society itself. Objective: The aim of our systematic review was to study the impact of the COVID-19 pandemic period on head and neck cancer patients, the effects on the health care provided and on patient health. Materials and Methods: This systematic review was based on the PRISMA guidelines and PICO strategy, with the focus question, “How has the COVID-19 pandemic period conditioned the treatment of patients with head and neck carcinoma?” Thus, electronic research was carried out on six databases: LILACS, PubMed/MedLine, Web of Science, the Cochrane COVID-19 Study Register, Scielo, and Scopus, aiming to answer the research question by considering the objective and defined criteria. The following information was extracted: author and year of the publication, patients’ age, gender, time until the first appointment, time from the first appointment to the surgery, the period in the hospital, time in intensive care, TNM, general stage of cancer, diagnostic procedures, oncological procedures, reconstructive surgery, and postoperative complications. Results: Initially, 837 articles were found. After removing duplicates, we obtained 471 studies. After screening by title and abstract, 67 articles were selected for full-text reading (k = 92) in order to assess their eligibility. Thus, nine articles were included (k = 1.0). All data and statistical results were obtained and contrasted. The included studies made it possible to reveal distinct impacts felt in different institutions of several countries, not allowing generalizable conclusions to be drawn. However, some of the variables analyzed are worrying, namely, the limitations that occurred in some types of oncological surgeries, as well as the increase in the number of patients admitted with higher TNM classifications and more debilitated general conditions. Conclusion: Within the limitation of this review, the results showed efforts made to prevent the pandemic from affecting the healthcare provided. There were no significant differences in days inside the intensive care unit, postoperative complications, and, in most cases, length of stay in the hospital. There were no differences in the number of patients admitted with a history of recurrence or neoadjuvant treatment. However, some variables raise concerns, such as the increase in patients with more advanced stage and TNM classification and a decrease in certain oncological procedures.

Introduction: Salivary gland neoplasms (SGN) represent a heterogeneous group of lesions. The identification of the genetic profile of tumors using immunohistochemistry (IHC) has been considered a tool in diagnostic pathology as well as a screen method in personalized medicine. The aim of this study was to evaluate the expression profile of two novel antibodies (pan-Trk and NOR-1) in a cohort of SGN. The hypothesis underlying this study is that pan-Trk is a marker for tumors harboring NTRK3 fusions, e.g. secretory carcinoma of the salivary glands (SC), and NOR-1 is a marker for lesions showing overexpression of NR4A3, e.g. acinic cell carcinoma (ACC). Materials and methods: Clinicopathological data and tissue blocks from 119 SGN cases were retrieved and organized in tissue microarray (TMA) blocks; IHC for pan-Trk and NOR-1 was performed and the pattern of staining (i.e. nuclear, cytoplasmic, and/or membranous) as well as intensity were quantified. Results: Pan-Trk showed nuclear positivity in all SC. However, a subset of ACC cases also showed nuclear expression for this marker. Cytoplasmic/membranous reactivity was observed in other SGN. The association of pan-Trk in detecting SC was significant (nuclear staining, P<0.003) and border significant (any staining, P=0.0484). NOR-1 showed nuclear expression in all ACC cases analyzed, with a sensitivity of 100% and specificity of 91.7% in detecting this lesion. Scattered, weak nuclear expression of NOR-1 was also observed in other SGN. All SC cases were negative for NOR-1. Conclusion: Diffuse and nuclear expression of NOR-1 is a sensitive and specific marker for ACC. Pan-Trk expression is heterogeneous across SGN, which may indicate the presence of different fusion partners to NTRK. The role of pan-Trk as a single marker for the diagnosis of SC is unclear. The use of both markers in combination may be an alternative approach for the distinction between SC and ACC.

Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return. Here we show that expression of SRY-box transcription factor 2 (SOX2) in precancerous lesions imparts an irreversible risk that recruits suppressive myeloid cells by promoting the release of CCL2. We developed a unique genetically engineered mouse model (GEMM) to recapitulate the malignant transformation of epithelial dysplasia to SCC in the oral mucosa with high histologic and phenotypic fidelity. Using a combination of longitudinal human specimens and the Sox2-GEMM, we found that the myeloid cells in precancerous epithelial dysplasia exhibit a distinctive dichotomous profile featuring high levels of IL-1α-SLC2A1 and low levels of type-I interferon (IFN-I) signatures, which occurs before SCC emerges histologically. Brief priming of myeloid cells with IL-1α desensitizes them to IFN-I agonists and makes myeloid-derived suppressor cells (MDSC) even more suppressive of T-cell activation. Mechanistically, IL-1 activation represses the expression of DHHC3/7 enzymes, which are responsible for the palmitoylation of stimulator of interferon genes (STING). Early blockade of IL1 signaling using pharmacologic and genetic approaches similarly reduces MDSC and SLC2A1 myeloid cells, suppresses epithelial dysplasia transformation, and extends survival. This work establishes a previously unrecognized SOX2-CCL2-IL1 pathway that leads to irreversible immune escape when precancerous epithelial lesions transform.

The massive galaxy cluster El Gordo (z = 0.87) imprints multitudes of gravitationally lensed arcs onto James Webb Space Telescope Near-Infrared Camera (NIRCam) images. Eight bands of NIRCam imaging were obtained in the “Prime Extragalactic Areas for Reionization and Lensing Science” (“PEARLS”) program. Point-spread function–matched photometry across Hubble Space Telescope and NIRCam filters supplies new photometric redshifts. A new light-traces-mass lens model based on 56 image multiplicities identifies the two mass peaks and yields a mass estimate within 500 kpc of (7.0 ± 0.30) × 1014 M ⊙. A search for substructure in the 140 cluster members with spectroscopic redshifts confirms the two main mass components. The southeastern mass peak that contains the brightest cluster galaxy is more tightly bound than the northwestern one. The virial mass within 1.7 Mpc is (5.1 ± 0.60)×1014 M ⊙, lower than the lensing mass. A significant transverse velocity component could mean the virial mass is underestimated. We contribute one new member to the previously known z = 4.32 galaxy group. Intrinsic (delensed) positions of the five secure group members span a physical extent of ∼60 kpc. 13 additional candidates selected by spectroscopic/photometric constraints are small and faint, with a mean intrinsic luminosity ∼2.2 mag fainter than L *. NIRCam imaging admits a fairly wide range of brightnesses and morphologies for the group members, suggesting a more diverse galaxy population in this galaxy overdensity.