scholarly journals Microneedle-mediated intratumoral delivery of anti-CTLA-4 promotes cDC1-dependent eradication of oral squamous cell carcinoma with limited irAEs

2021 ◽  
Author(s):  
Mara Gilardi ◽  
Robert Saddawi-Konefka ◽  
Victoria H. Wu ◽  
Miguel Angel Lopez-Ramirez ◽  
Zhiyong Wang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Therapy Termination ◽  
Cell Immunity ◽  
Life Threatening

AbstractHead and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Immunotherapies – principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity – offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first line treatment of recurrent and metastatic HNSCC; however less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAEs) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life-threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.

scholarly journals Actual treatment options for locally advanced and metastatic cutaneous squamous cell carcinoma

2021 ◽  
Vol 23 (1) ◽  
pp. 94-98
Author(s):  
Anastasia V. Ignatova
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Locally Advanced ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Molecular Profile ◽  
New Information ◽  
New Treatment

Squamous cell carcinoma of the skin, or cutaneous squamous cell carcinoma (CSCC), is the second most frequent type of skin cancer, and its incidence continues to rise all over the world. Usually has a benign clinical behavior, but it can be presented as locally invasive and metastatic aggressive tumor with 2% mortality rate. Nowadays, new risk factors for have appeared, that form pharmacologically-induced CSCC after immunosuppressant drugs used for organ transplantation, or BRAF inhibitors used for melanoma. In recent years we have got a new information about the role of mutational burden, signaling pathways involved in CSCC development and new possibilities and molecules for targeted therapy. Better understanding of the immune system functioning and benefits of immunotherapy with immune checkpoint inhibitors (PD-1) for CSCC that has changed the therapeutic approach. According to recent clinical trials data, new treatment options with PD-1 inhibitors achieved a response rate of 50% for locally advanced CSCC and 47% for metastatic CSCC, including 16.1% complete remissions. This review focuses on the molecular profile, targeted therapies and immunotherapy for locally advanced and metastatic CSCC.

scholarly journals Prognostic and Predictive Factors in Advanced Head and Neck Squamous Cell Carcinoma

2021 ◽  
Vol 22 (9) ◽  
pp. 4981
Author(s):  
Teresa Magnes ◽  
Sandro Wagner ◽  
Dominik Kiem ◽  
Lukas Weiss ◽  
Gabriel Rinnerthaler ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Locally Advanced ◽  
Neck Squamous Cell Carcinoma ◽  
Upper Aerodigestive Tract ◽  
Hpv Status

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.

Comparison of in vivo and in vitro prostaglandin E production by squamous cell carcinoma of the head and neck

1994 ◽  
Vol 111 (3) ◽  
pp. 189-196 ◽  
Author(s):  
C SNYDERMAN ◽  
I KLAPAN ◽  
M MILANOVICH ◽  
D HEO ◽  
R WAGNER ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Prostaglandin E

Corilagin Inhibits Esophageal Squamous Cell Carcinoma by Inducing DNA Damage and Down-Regulation of RNF8

2019 ◽  
Vol 19 (8) ◽  
pp. 1021-1028 ◽  
Author(s):  
Fanghua Qiu ◽  
Lifang Liu ◽  
Yu Lin ◽  
Zetian Yang ◽  
Feng Qiu
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cell Apoptosis ◽  
Cell Counting ◽  
Antitumor Effects

Background:Esophageal squamous cell carcinoma (ESCC), the most prevalent histologic subtype of esophageal cancer, is an aggressive malignancy with poor prognosis and a high incidence in the East. Corilagin, an active component present in Phyllanthus niruri L., has been shown to suppress tumor growth in various cancers. However, the effects of corilagin on ESCC and the mechanisms for its tumor suppressive function remain unknown.Methods:Cell proliferation was measured by Cell Counting Kit-8 assay and colony formation assays. Annexin V/PI double-staining was performed to assess cell apoptosis. Immunofluorescence staining and western blotting were used to evaluate the protein expression. A xenograft mice model was used to assess the in vivo antitumor effects of corilagin alone or in combination with cisplatin.Results:We for the first time showed that corilagin was effectively able to inhibit ESCC cell proliferation and induce cell apoptosis. Additionally, our results validated its antitumor effects in vivo using a xenograft mouse model. Mechanistically, we found that corilagin caused significant DNA damage in ESCC cells. We found that corilagin could significantly attenuate the expression of the E3 ubiquitin ligase RING finger protein 8 (RNF8) through ubiquitin-proteasome pathway, leading to the inability of DNA damage repair response and eventually causing cell apoptosis. Furthermore, we also showed that corilagin substantially enhanced the antitumor effects of chemotherapy drug cisplatin both in vitro and in vivo.Conclusion:Our results not only provided novel and previously unrecognized evidences for corilagin-induced tumor suppression through inducing DNA damage and targeting RNF8 in ESCC, but also highlighted that corilagin might serve as an adjunctive treatment to conventional chemotherapeutic drugs in ESCC patients.

scholarly journals Methyltransferase like 13 mediates the translation of Snail in head and neck squamous cell carcinoma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaochen Wang ◽  
Kang Li ◽  
Yuehan Wan ◽  
Fangfang Chen ◽  
Maosheng Cheng ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Neck Squamous Cell Carcinoma ◽  
Translation Efficiency ◽  
Mechanism Study ◽  
Clinical Prognosis ◽  
Cellular Phenotypes

AbstractMethyltransferase like 13 (METTL13), a kind of methyltransferase, is implicated in protein binding and synthesis. The upregulation of METTL13 has been reported in a variety of tumors. However, little was known about its potential function in head and neck squamous cell carcinoma (HNSCC) so far. In this study, we found that METTL13 was significantly upregulated in HNSCC at both mRNA and protein level. Increased METTL13 was negatively associated with clinical prognosis. And METTL13 markedly affected HNSCC cellular phenotypes in vivo and vitro. Further mechanism study revealed that METTL13 could regulate EMT signaling pathway by mediating enhancing translation efficiency of Snail, the key transcription factor in EMT, hence regulating the progression of EMT. Furthermore, Snail was verified to mediate METTL13-induced HNSCC cell malignant phenotypes. Altogether, our study had revealed the oncogenic role of METTL13 in HNSCC, and provided a potential therapeutic strategy.

scholarly journals Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323276
Author(s):  
Jin Zhou ◽  
Zhong Wu ◽  
Zhouwei Zhang ◽  
Louisa Goss ◽  
James McFarland ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Large Scale ◽  
Cell Cancer ◽  
Oesophageal Squamous Cell Carcinoma ◽  
Squamous Cancer ◽  
Striking Success

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

scholarly journals Inhibited MicroRNA-301 Restrains Angiogenesis and Cell Growth in Esophageal Squamous Cell Carcinoma by Elevating PTEN

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bin Wang ◽  
Peiyan Hua ◽  
Ruimin Wang ◽  
Jindong Li ◽  
Guangxin Zhang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Growth ◽  
Esophageal Squamous Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cell Cycle Distribution ◽  
Pten Inhibition ◽  
The Impact

Abstract Objective Esophageal squamous cell carcinoma (ESCC) is featured by early metastasis and late diagnosis. MicroRNA-301 (miR-301) is known to participate in diverse cancers. Nevertheless, effects of miR-301 on ESCC remain unexplored. Thus, we aim to explore the role of miR-301 in ESCC progression. Methods Expression of miR-301 and phosphatase and tensin homologue (PTEN) in ESCC tissues and cell lines was assessed. Next, the screened cells were treated with altered miR-301 or PTEN oligonucleotide and plasmid, and then, the colony formation ability, cell viability, migration, invasion, cell cycle distribution and apoptosis of ESCC cells were assessed. Moreover, tumor growth and microvessel density (MVD) were also assessed, and the targeting relationship between miR-301 and PTEN was affirmed. Results MiR-301 was upregulated, and PTEN was downregulated in ESCC tissues and cells. KYSE30 cells and Eca109 cells were selected for functional assays. In KYSE30 cells, inhibited miR-301 or overexpressed PTEN suppressed cell malignant behaviors, and silenced PTEN eliminated the impact of miR-301 inhibition on ESCC progression. In Eca109 cells, miR-301 overexpression or PTEN inhibition promoted cell malignant behaviors, and PTEN overexpression reversed the effects of miR-301 elevation on ESCC progression. The in vivo assay revealed that miR-301 inhibition or PTEN overexpression repressed ESCC tumor growth and MVD, and miR-301 elevation or PTEN reduction had contrary effects. Moreover, PTEN was targeted by miR-301. Conclusion Taken together, results in our study revealed that miR-301 affected cell growth, metastasis and angiogenesis via regulating PTEN expression in ESCC.

scholarly journals JOSD1 promotes proliferation and chemoresistance of head and neck squamous cell carcinoma under the epigenetic regulation of BRD4

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chao Jing ◽  
Dandan Liu ◽  
Qingchuan Lai ◽  
Linqi Li ◽  
Mengqian Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Gene Expression Omnibus ◽  
Neck Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
In Vivo Experiments

Abstract Background Deubiquitinating enzymes (DUBs) play critical roles in various cancers by modulating functional proteins post-translationally. Previous studies have demonstrated that DUB Josephin Domain Containing 1 (JOSD1) is implicated in tumor progression, however, the role and mechanism of JOSD1 in head and neck squamous cell carcinoma (HNSCC) remain to be explored. In this study, we aimed to identify the clinical significance and function of JOSD1 in HNSCC. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to find novel DUBs in HNSCC. Immunohistochemistry assay was performed to determine the expression of JOSD1 in our cohort of 42 patients suffered with HNSCC. Kaplan–Meier analysis was used to identify the correlation between JOSD1 and the prognosis of HNSCC patients. The regulation of BRD4 on JOSD1 was determined by using pharmacological inhibition and gene depletion. The in vitro and in vivo experiments were conducted to elucidate the role of JOSD1 in HNSCC. Results The results of IHC showed that JOSD1 was aberrantly expressed in HNSCC specimens, especially in the chemoresistant ones. The overexpression of JOSD1 indicated poor clinical outcome of HNSCC patients. Moreover, JOSD1 depletion dramatically impaired cell proliferation and colony formation, and promoted cisplatin-induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity in vivo. The epigenetic regulator BRD4 contributed to the upregulation of JOSD1 in HNSCC. Conclusions These results demonstrate that JOSD1 functions as an oncogene in HNSCC progression, and provide a promising target for clinical diagnosis and therapy of HNSCC.

scholarly journals Squamous cell carcinoma of the scrotum in HIV: two case reports

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jeff John ◽  
Ken Kesner ◽  
John Lazarus
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Case Reports ◽  
Treatment Options ◽  
Punch Biopsy ◽  
Delayed Treatment ◽  
Clinical Presentations ◽  
T1 N0 M0

Abstract Background Squamous cell carcinoma (SCC) of the scrotum was the first malignancy known to be associated with exposure to an occupational carcinogen—in this case, soot trapped in the breeches of chimney sweeps. Better civil rules and regulations and the replacement of hearths with other forms of heating have rendered SCC of the scrotum a rarity. We report two cases of scrotal SCC with vastly differing clinical presentations and management. Case presentation Case 1 had T1 N0 M0 disease and presented with a small (< 2 cm), innocuous-looking, non-healing ulcer of eight years duration. A punch biopsy revealed a superficially invasive SCC confirmed on immunohistochemical profiling. A wide local excision of the lesion was subsequently performed. Follow-up at three years showed no signs of recurrence. Case 2 presented with T4 N1 M1 disease and rapidly progressing locally destructive mass. A punch biopsy of the scrotal lesion confirmed invasive moderately differentiated focally keratinising SCC. The metastatic evaluation confirmed the presence of metastatic, extensive para-aortic lymphadenopathy. He was managed with cisplatin-based chemoradiotherapy. Conclusion Early detection and management of patients with SCC of the scrotum are essential. If the diagnosis is delayed, treatment options become limited, and the prognosis is poor. Notwithstanding the rarity of this disease, multicentre trials are needed to provide more precise guidelines as to the optimal management of these patients.

scholarly journals Neoadjuvant immunotherapy in resectable head and neck cancer: oral cavity carcinoma as a potential research model

2021 ◽  
Vol 13 ◽  
pp. 175883592098406
Author(s):  
Vanesa Gutiérrez Calderón ◽  
Alexandra Cantero González ◽  
Laura Gálvez Carvajal ◽  
Yolanda Aguilar Lizarralde ◽  
Antonio Rueda Domínguez
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Surgical Resection ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Research Model

Squamous cell carcinoma of oral cavity (OCSCC) accounts for approximately 25% of cases of head and neck squamous cell carcinoma (HNSCC). Tobacco and alcohol consumption are the main risk factors for both cancers. Surgical resection, combined with adjuvant radiotherapy or radiochemotherapy in patients with high risk of relapse, is the key element in management in the initial stages. However, despite the availability of aggressive multidisciplinary treatments, advanced resectable OCSCC carries poor prognosis; only half of the patients are disease-free 5 years after the surgery. Immunotherapy based on the use of immune checkpoint inhibitors has been proven to be effective in a wide variety of tumours, including recurrent and metastatic HNSCC. These positive results resulted in investigations into its effectiveness in earlier stages of the disease with OCSCC emerging as an interesting research model because of the accessible location of the tumours. This article reviews the potential advantages of emerging immunotherapeutic agents [mainly monoclonal antibodies against programmed cell death-1 ( PD-1) immune checkpoint inhibitors] as neoadjuvant treatment for OCSCC at locoregional stages as well as the ongoing clinical trials, challenges in evaluating tumour response, and possible predictive biomarkers of response with highlights regarding the role of oral microbiota as modulators of immune response. The efficacy and safety of anti- PD-1 drugs in these patients have been proven in preliminary trials. If there is a decrease in the relapse rate and an improvement in the overall survival after surgical resection in ongoing trials, preoperative immunotherapy may be established as a treatment option for patients with early stages of the disease.

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