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1
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Association of PD-L1 gene polymorphisms and circulating sPD-L1 levels with HBV infection susceptibility and related liver disease progression. Gene 2022; 806:145935. [PMID: 34478821 DOI: 10.1016/j.gene.2021.145935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023]
Abstract
Soluble molecules of programmed death ligand 1 (sPD-L1) are known to modulate T-cell depletion, an important mechanism of hepatitis B virus (HBV) persistence and liver disease progression. In addition, PD-L1 polymorphisms in the 3'-UTR can influence PD-L1 expression and have been associated with cancer risk, although not definitively. The purpose of this study was to investigate the association of PD-L1 polymorphisms and circulating levels of sPD-L1 in HBV infection and live disease progression. In this study, five hundred fifty-one HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 186), liver cirrhosis (LC, n = 142) and hepatocellular carcinoma (HCC, n = 223) and 240 healthy individuals (HC) were enrolled. PD-L1 polymorphisms (rs2297136 and rs4143815) were genotyped by in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of PD-L1 polymorphisms with HBV infection as well as with progression of related liver diseases. Plasma sPD-L1 levels were quantified by ELISA assays. The PD-L1 rs2297136 AA genotype was associated with HBV infection susceptibility (HBV vs. HC: OR = 1.6; 95%CI = 1.1-2.3; p = 0.0087) and disease progression (LC vs. CHB: OR = 1.8; 95%CI = 1.1-2.9; p = 0.018). Whereas, the rs2297136 GG genotype was a protective factor for HCC development. Plasma sPD-L1 levels were significantly high in HBV patients (p < 0.0001) and higher in the LC followed by CHB and HCC groups. High sPD-L1 levels correlated with increased liver enzymes and with advanced liver disease progression (Child-pugh C > B > A, p < 0.0001) and BCLC classification (BCLC D > C > B > A, p = 0.031). We could, for the first time, conclude that PD-L1 rs2297136 polymorphism and plasma sPD-L1 protein levels associate with HBV infection and HBV-related liver disease progression.
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PD-L1: Can it be a biomarker for the prognosis or a promising therapeutic target in cervical cancer? Int Immunopharmacol 2021; 103:108484. [PMID: 34954558 DOI: 10.1016/j.intimp.2021.108484] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/12/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022]
Abstract
Cervical cancer is one of the most common in the female genital tract and remains a leading cause that threatens the health and lives of women worldwide, although preventive vaccines and early diagnosis have reduced mortality. While treatment by operation and chemoradiotherapy for early-stage patients achieve good outcomes, the great majority of cervical cancers caused by the human papilloma virus (HPV) make immunotherapy realizable for patients with advanced and recurrent cervical cancer. To date, some clinical trials of checkpoint immunotherapy in cervical cancer have indicated significant benefits of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors, providing strong evidence for PD-1/PD-L1 as a therapeutic target. In this review article, we discuss the role of PD-L1 and the application of PD-L1 inhibitors in cervical cancer, with the aim of providing direction for future research.
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Knochelmann HM, Horton JD, Liu S, Armeson K, Kaczmar JM, Wyatt MM, Richardson MS, Lomeli SH, Xiong Y, Graboyes EM, Lentsch EJ, Hornig JD, Skoner J, Stalcup S, Spampinato MV, Garrett-Mayer E, O’Quinn EC, Timmers CD, Romeo MJ, Wrangle JM, Young MRI, Rubinstein MP, Day TA, Lo RS, Paulos CM, Neskey DM. Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma. Cell Rep Med 2021; 2:100426. [PMID: 34755137 PMCID: PMC8561313 DOI: 10.1016/j.xcrm.2021.100426] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/02/2021] [Accepted: 09/23/2021] [Indexed: 01/19/2023]
Abstract
Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon's two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%-53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).
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MESH Headings
- Aged
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/immunology
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/surgery
- Cohort Studies
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immune Checkpoint Inhibitors/therapeutic use
- Male
- Middle Aged
- Mouth Neoplasms/drug therapy
- Mouth Neoplasms/immunology
- Mouth Neoplasms/mortality
- Mouth Neoplasms/surgery
- Neoadjuvant Therapy/methods
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/surgery
- Neoplasm Staging
- Nivolumab/therapeutic use
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/immunology
- Survival Analysis
- Treatment Outcome
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Affiliation(s)
- Hannah M. Knochelmann
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Surgery – Oncology, Emory University, Atlanta, GA, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Joshua D. Horton
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Sixue Liu
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Kent Armeson
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - John M. Kaczmar
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Megan M. Wyatt
- Department of Surgery – Oncology, Emory University, Atlanta, GA, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Mary S. Richardson
- Department of Pathology, Medical University of South Carolina, Charleston, SC, USA
| | - Shirley H. Lomeli
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ying Xiong
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Evan M. Graboyes
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Eric J. Lentsch
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Joshua D. Hornig
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Judith Skoner
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Seth Stalcup
- Department of Radiology, Medical University of South Carolina, Charleston, SC, USA
| | - Maria V. Spampinato
- Department of Radiology, Medical University of South Carolina, Charleston, SC, USA
| | | | - Elizabeth C. O’Quinn
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Cynthia D. Timmers
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Martin J. Romeo
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - John M. Wrangle
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - M. Rita I. Young
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Mark P. Rubinstein
- Translational Therapeutics, The Ohio State University, The James Comprehensive Cancer Center, Columbus, OH, USA
| | - Terry A. Day
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Roger S. Lo
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Chrystal M. Paulos
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Surgery – Oncology, Emory University, Atlanta, GA, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - David M. Neskey
- Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
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Zhang L, Zhao Y, Tu Q, Xue X, Zhu X, Zhao KN. The Roles of Programmed Cell Death Ligand-1/ Programmed Cell Death-1 (PD-L1/PD-1) in HPV-induced Cervical Cancer and Potential for their Use in Blockade Therapy. Curr Med Chem 2021; 28:893-909. [PMID: 32003657 DOI: 10.2174/0929867327666200128105459] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/13/2019] [Accepted: 12/14/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but the outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. METHODS We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. RESULTS One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signalling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and microRNA, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in the immune escape of cervical cancer through inhibition of host immune response. Creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for the therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PDL1/ PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. CONCLUSION Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body's immune system to fight cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.
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Affiliation(s)
- Lifang Zhang
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China
| | - Yu Zhao
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Quanmei Tu
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Xiangyang Xue
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China
| | - Xueqiong Zhu
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Kong-Nan Zhao
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China
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Delafoy A, Uguen A, Lemasson G, Conan-Charlet V, Pradier O, Lucia F, Schick U. PD-L1 expression in recurrent head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2021; 279:343-351. [PMID: 33796940 DOI: 10.1007/s00405-021-06777-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/20/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE To evaluate the Programmed Cell Death Ligand (PD-L1) expression at diagnosis and relapse in patients with head and neck carcinoma (HNSCC) treated with radio(chemo)therapy. METHODS PD-L1 immunohistochemistry was performed in tumor cells (TC) and immune cells (IC) in 44 patients and scored as 0 = 0%, 1 = < 5%, 2 = 6-49% or 3 = ≥ 50% cells. RESULTS PD-L1 expression on TC before RT was scored as 0, 1, 2 and 3 in 28, 4, 8 and 4 patients, respectively. In 10 patients, IC did not show any PD-L1 expression; while in 8, 16, and 10 patients, PD-L1 expression was scored 1, 2 and 3, respectively. At relapse, 7/36 patients had a PD-L1 expression positivation in TC, while the opposite was observed in 6 patients. Overall, survival at 2 years was higher in patients with PD-L1 expression (90% versus 62.5%, p = 0.032). CONCLUSION PD-L1 expression may vary throughout the course of the disease. A re-evaluation of PD-L1 expression on biopsies at the time of recurrence should be recommended.
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Affiliation(s)
- Alice Delafoy
- Radiation Oncology Department, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France
| | - Arnaud Uguen
- Department of Pathology, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France
| | - Gilles Lemasson
- Department of Pathology, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France
| | - Virginie Conan-Charlet
- Department of Pathology, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France
| | - Olivier Pradier
- Radiation Oncology Department, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France.,LaTIM, INSERM, UMR 1101, University of Brest, ISBAM, UBO, UBL, Brest, France
| | - François Lucia
- Radiation Oncology Department, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France. .,LaTIM, INSERM, UMR 1101, University of Brest, ISBAM, UBO, UBL, Brest, France.
| | - Ulrike Schick
- Radiation Oncology Department, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France.,LaTIM, INSERM, UMR 1101, University of Brest, ISBAM, UBO, UBL, Brest, France
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6
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Evrard D, Hourseau M, Couvelard A, Paradis V, Gauthier H, Raymond E, Halimi C, Barry B, Faivre S. PD-L1 expression in the microenvironment and the response to checkpoint inhibitors in head and neck squamous cell carcinoma. Oncoimmunology 2020; 9:1844403. [PMID: 33299655 PMCID: PMC7714503 DOI: 10.1080/2162402x.2020.1844403] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
In head and neck squamous cell carcinoma (HNSCC), data from studies using checkpoint-inhibiting antibodies that target programmed death 1 (PD-1) or its ligand the programmed death ligand 1 (PD-L1) demonstrated outstanding clinical activity. Translational investigations also suggested some correlations between therapeutic response and PD-L1 expression in tumor tissue. We comprehensively summarize results that have evaluated PD-L1 expression in HNSCC. We discuss flaws and strength of current PD-1/PD-L1 detection, quantification methods and the evaluation of PD-L1 as a prognostic and theragnostic biomarker. Understanding tumor microenvironment may help understanding resistance to checkpoint inhibitors, designing clinical trials that can exploit drug combinations.
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Affiliation(s)
- D Evrard
- Department of Otorhinolaryngology, Bichat Hospital, Paris, France
| | - M Hourseau
- Pathology Department, Bichat Hospital, Paris 7 University, Paris, France
| | - A Couvelard
- Pathology Department, Bichat Hospital, Paris 7 University, Paris, France
| | - V Paradis
- Pathology Department, Beaujon Hospital, Paris 7 University, Paris, France
| | - H Gauthier
- Medical Oncology Department, Saint-Louis Hospital, Paris 7 University, Paris, France
| | - E Raymond
- Medical Oncology Department, Paris-St Joseph Hospital, Paris, France
| | - C Halimi
- Department of Otorhinolaryngology, Bichat Hospital, Paris, France
| | - B Barry
- Department of Otorhinolaryngology, Bichat Hospital, Paris, France
| | - S Faivre
- Medical Oncology Department, Saint-Louis Hospital, Paris 7 University, Paris, France
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7
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Qiao XW, Jiang J, Pang X, Huang MC, Tang YJ, Liang XH, Tang YL. The Evolving Landscape of PD-1/PD-L1 Pathway in Head and Neck Cancer. Front Immunol 2020; 11:1721. [PMID: 33072064 PMCID: PMC7531035 DOI: 10.3389/fimmu.2020.01721] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/29/2020] [Indexed: 02/05/2023] Open
Abstract
Over the past 10 years, cancer immunotherapy has made significant progress in multiple cancer types and has been gradually been applied to clinical cancer care, in which the programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is one of the most attractive targets. Compared with traditional therapies, the emerging PD-1/PD-L1 blockade immunotherapy exhibited more satisfactory curative effects and lower toxicity for patients with advanced head and neck squamous cell carcinoma (HNSCC). This review analyzes the expression characteristics and clinical significance of PD-1/PD-L1 in HNSCC, the immunosuppressive roles of tumor cell and stromal cell expressing PD-1/PD-L1 in this disease, and presents the development landscape of PD-1/PD-L1 inhibitors, which may provide new curative alternatives for recurrent or metastatic HNSCC.
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Affiliation(s)
- Xin-Wei Qiao
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jian Jiang
- Department of Head and Neck Surgery, Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu, China
| | - Xin Pang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mei-Chang Huang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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8
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Immune Checkpoint Inhibitors in Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review. Cancers (Basel) 2020; 12:cancers12071937. [PMID: 32708945 PMCID: PMC7409293 DOI: 10.3390/cancers12071937] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/12/2020] [Accepted: 07/16/2020] [Indexed: 12/18/2022] Open
Abstract
Cancers of the oral cavity cause significant cancer-related death worldwide. While survival rates have improved in recent years, new methods of treatment are being investigated to limit disease progression and to improve outcomes, particularly in oral cavity squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD). The emerging treatment modality of immunotherapy targets immune checkpoint molecules including PD-1 and its ligand PD-L1, CTLA-4, LAG-3, and TIM-3 to enhance the host immune response against tumours, and to limit the growth and progression of cancer cells. In this systematic review, we searched five databases for keywords pertaining to oral cancers and OPMDs, along with immune checkpoint inhibitors, in order to summarize the current status of their use and efficacy in these diseases. A total of 644 different articles were identified between 2004 and 2019, with 76 deemed suitable for inclusion in the study, providing a total of 8826 samples. Combined results show expression of PD-1 and PD-L1 in the majority of OPMD and OSCC samples, with expression correlating with increased progression and decreased survival rates. Immunotherapy agents pembrolizumab and nivolumab target PD-1 and have been shown to prolong survival rates and improve disease outcomes, especially in combination with chemotherapy or radiotherapy. Despite the equivocal nature of current evidence, there is support for the prognostic and predictive value of immune checkpoint molecules, especially PD-L1, and many studies provide support for the effective use of immune checkpoint inhibitors in the management of OSCC. Limited data is available for OPMD, therefore this should be the focus of future research.
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9
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Nasser H, St. John MA. The promise of immunotherapy in the treatment of young adults with oral tongue cancer. Laryngoscope Investig Otolaryngol 2020; 5:235-242. [PMID: 32337355 PMCID: PMC7178456 DOI: 10.1002/lio2.366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 02/10/2020] [Accepted: 02/12/2020] [Indexed: 12/12/2022] Open
Abstract
Historically considered a disease of the older male resulting from cumulative tobacco and alcohol use, more recently we have witnessed a rise in the global incidence of oral tongue squamous cell carcinoma in younger adults, particularly those without any identifiable risk factor exposure. These patients appear to be at higher overall risk for locoregional treatment failure and often experience a more heterogeneous clinical course, with some afflicted with particularly aggressive, rapidly progressive disease. Recent research efforts have supported the idea that although this disease may be genomically similar in these groups, and molecular differences in the tumor immune microenvironment may account for biological differences between young and older patients, as well as patients with and without exposure to alcohol or tobacco. In this review, we seek to summarize current knowledge regarding pathogenesis of oral tongue carcinoma in the young adult patient and examine the potential role of the immune response in disease progression and as a target for novel immunotherapies.
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Affiliation(s)
- Hassan Nasser
- UCLA Head and Neck Cancer ProgramRonald Reagan Medical CenterLos AngelesCalifornia
| | - Maie A. St. John
- UCLA Head and Neck Cancer ProgramRonald Reagan Medical CenterLos AngelesCalifornia
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10
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PD-L1 Detection-Pearls and Pitfalls Associated With Current Methodologies Focusing on Entities Relevant to Dermatopathology. Am J Dermatopathol 2020; 41:539-565. [PMID: 31335407 DOI: 10.1097/dad.0000000000001287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PD-L1 is a transmembrane glycoprotein with an extracellular as well as an intracellular cytoplasmic domain. Physiologically, it plays a pivotal role in regulating T-cell activation and tolerance. Many tumor cells have exploited this regulatory mechanism by overexpressing PD-L1 in an effort to escape immunologic surveillance. In this review, we parse the literature regarding the prognostic value of tumoral PD-L1 expression before discussing the various methodologies as well as the pearls and pitfalls associated with each for predicting response to anti-PD-1/PD-L1 therapies. Special attention is given to cutaneous entities in which PD-L1 expression has been documented with an emphasis on cutaneous malignancies that have seen the broadest applications of anti-PD-L1/PD-1 therapies. Currently, immunohistochemistry is the method that is most commonly used for detection of PD-L1. However, with the wide array of immunohistochemistry protocols and staining platforms available in the market, there seems to be different cutoffs not just for different entities but also for the same entity. This review is an attempt to address the need for standardization and validation of existing protocols for PD-L1 detection.
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11
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Liao P, Wang H, Tang YL, Tang YJ, Liang XH. The Common Costimulatory and Coinhibitory Signaling Molecules in Head and Neck Squamous Cell Carcinoma. Front Immunol 2019; 10:2457. [PMID: 31708918 PMCID: PMC6819372 DOI: 10.3389/fimmu.2019.02457] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/01/2019] [Indexed: 02/05/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are closely linked with immunosuppression, accompanied by complex immune cell functional activities. The abnormal competition between costimulatory and coinhibitory signal molecules plays an important role in the malignant progression of HNSCC. This review will summarize the features of costimulatory molecules (including CD137, OX40 as well as CD40) and coinhibitory molecules (including CTLA-4, PD-1, LAG3, and TIM3), analyze the underlying mechanism behind these molecules' regulation of the progression of HNSCC, and introduce the clinic application. Vaccines, such as those targeting STING while working synergistically with monoclonal antibodies, are also discussed. A deep understanding of the tumor immune landscape will help find new and improved tumor immunotherapy for HNSCC.
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Affiliation(s)
- Peng Liao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Haofan Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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12
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Nagarajan P, El-Hadad C, Gruschkus SK, Ning J, Hudgens CW, Sagiv O, Gross N, Tetzlaff MT, Esmaeli B. PD-L1/PD1 Expression, Composition of Tumor-Associated Immune Infiltrate, and HPV Status in Conjunctival Squamous Cell Carcinoma. Invest Ophthalmol Vis Sci 2019; 60:2388-2398. [PMID: 31141610 PMCID: PMC6890426 DOI: 10.1167/iovs.19-26894] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose Conjunctival squamous cell carcinoma (SCC), a type of ocular surface neoplasia, is primarily treated by surgical resection and topical immuno- or chemotherapy. Metastatic disease may be treated with systemic chemo- or immunotherapy, albeit with variable response. The purpose of this study was to determine whether immune checkpoint blockade might be considered in the management of conjunctival SCC. Methods In this retrospective study, we evaluated tumor programmed death-ligand 1 (PD-L1) expression, high-risk human papillomavirus (HPV) status, and immunohistochemical expression of cluster of differentiation 3 (CD3), cluster of differentiation 8 (CD8), and programmed death 1 (PD1) in tumor-associated immune infiltrate in a series of 31 conjunctival SCCs. Results PD-L1 expression in ≥1% of tumor cells was noted in 14 conjunctival SCCs (47%) and was more prevalent in invasive than in situ SCC and among tumors with higher American Joint Committee on Cancer (AJCC) T category (≥T3 versus ≤T2). The density of CD3-positive T cells was higher in primary than recurrent tumors and higher in invasive than in situ tumors. Density of CD3-positive and CD8-positive T cells was higher in higher AJCC stage tumors. Density of CD8-positive T cells was higher in HPV-positive than HPV-negative tumors. PD-L1 expression correlated with a higher density of CD3-, CD8-, and PD1-positive cells in the tumor-associated immune infiltrate but not with HPV status. Conclusions Our findings demonstrate that PD-L1 is expressed in almost half of conjunctival SCCs. The density of tumor-associated immune cells correlated with invasive SCC, stage, and HPV status in conjunctival SCC. Our findings support further studies to establish the potential application of immune checkpoint blockade in the management of conjunctival SCC.
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Affiliation(s)
- Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Christian El-Hadad
- Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Stephen K Gruschkus
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Courtney W Hudgens
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Oded Sagiv
- Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Neil Gross
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Michael T Tetzlaff
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.,Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Bita Esmaeli
- Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
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13
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Gomez Hernandez MP, Bates AM, Starman EE, Lanzel EA, Comnick C, Xie XJ, Brogden KA. HBD3 Induces PD-L1 Expression on Head and Neck Squamous Cell Carcinoma Cell Lines. Antibiotics (Basel) 2019; 8:antibiotics8040161. [PMID: 31554151 PMCID: PMC6963492 DOI: 10.3390/antibiotics8040161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/13/2019] [Accepted: 09/19/2019] [Indexed: 12/21/2022] Open
Abstract
Human β-defensin 3 (HBD3) is an antimicrobial peptide up-regulated in the oral tissues of individuals with head and neck squamous cell carcinomas (HNSCC) and oral squamous cell carcinomas (SCC) and present in high concentrations in their saliva. In this study, we determined if HBD3 contributes to HNSCC pathogenesis by inducing programmed death-ligand 1 (PD-L1) expression on HNSCC cell lines. For this, SCC cell lines SCC4, SCC15, SCC19, SCC25, and SCC99 (5.0 × 104 viable cells) were used. Cells were incubated with IFNγ (0.6 µM) and HBD3 (0.2, 2.0, or 20.0 µM) for 24 h. Cells alone served as controls. Cells were then treated with anti-human APC-CD274 (PD-L1) and Live/Dead Fixable Green Dead Cell Stain. Cells treated with an isotype antibody and cells alone served as controls. All cell suspensions were analyzed in a LSR II Violet Flow Cytometer. Cytometric data was analyzed using FlowJo software. Treatment with IFNγ (0.6 µM) increased the number of cells expressing PD-L1 (p < 0.05) with respect to controls. Treatment with HBD3 (20.0 µM) also increased the number of cells expressing PD-L1 (p < 0.05) with respect to controls. However, treatment with IFNγ (0.6 µM) was not significantly different from treatment with HBD3 (20.0 µM) and the numbers of cells expressing PD-L1 were similar (p = 1). Thus, HBD3 increases the number of cells expressing PD-L1. This is a novel concept, but the role HBD3 contributes to HNSCC pathogenesis by inducing PD-L1 expression in tumors will have to be determined.
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Affiliation(s)
- Maria Paula Gomez Hernandez
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
| | - Amber M Bates
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
| | - Emily E Starman
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
| | - Emily A Lanzel
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
| | - Carissa Comnick
- Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
| | - Xian Jin Xie
- Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
| | - Kim A Brogden
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
- Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
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14
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Concurrent radiation therapy with programmed cell death protein 1 inhibition leads to a complete response in advanced cutaneous squamous cell carcinoma. JAAD Case Rep 2019; 5:763-766. [PMID: 31516991 PMCID: PMC6728732 DOI: 10.1016/j.jdcr.2019.06.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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15
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Sernicola A, Lampitelli S, Marraffa F, Maddalena P, Grassi S, Richetta AG, Calvieri S. Case Report: Cetuximab use in advanced cutaneous squamous cell carcinoma resistant to chemotherapy. F1000Res 2019; 8:933. [PMID: 32047600 PMCID: PMC6993817 DOI: 10.12688/f1000research.19149.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/06/2019] [Indexed: 11/20/2022] Open
Abstract
We present the case of a 60-year-old man with unresectable cutaneous squamous cell carcinoma (cSCC) of the sternal area, which was not amenable to radiation therapy (stage III, T3N0M0). The treatment history of this patient is remarkable as the disease had progressed through all lines of conventional therapy established in the literature. The patient was treated with epidermal growth factor receptor (EGFR) inhibitor cetuximab for 35 cycles and restaged after 12 months of therapy with a whole body CT scan, documenting stage IV disease (T3N2bM1). The use of cetuximab as a single agent was effective for a limited time and we decided to initiate combination therapy with cetuximab and nivolumab. Restaging after six months of this combination regimen documented stable disease.
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Affiliation(s)
- Alvise Sernicola
- Unit of Dermatology, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy
| | - Salvatore Lampitelli
- Unit of Dermatology, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy
| | - Federica Marraffa
- Unit of Dermatology, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy
| | - Patrizia Maddalena
- Unit of Dermatology, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy
| | - Sara Grassi
- Unit of Dermatology, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy
| | | | - Stefano Calvieri
- Unit of Dermatology, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy
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16
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Arriola AGP, Farahani SJ, Bhargava HK, Guzzo TJ, Brooks JSJ, Lal P. PD-L1 Expression Reveals Significant Association With Squamous Differentiation in Upper Tract Urothelial Carcinoma. Am J Clin Pathol 2019; 151:561-573. [PMID: 30776071 DOI: 10.1093/ajcp/aqz002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/16/2018] [Accepted: 01/10/2019] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Limited literature is available on the tumor microenvironment (TM) of upper tract urothelial carcinoma (UTUC). This study comprehensively reviews programmed death 1 receptor (PD-1)-positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE). METHODS Seventy-two nephroureterectomy specimens were analyzed for PD-L1, PD-1, and CD8. One percent or more tumor and lymphohistiocyte PD-L1 expression was considered positive. TIL density by H&E was scored semiquantitatively from 0 to 3, and CD8+ and PD-1+ TILs were quantified in hotspots. RESULTS Of the cases, 37.5% demonstrated PD-L1+ on TE. PD-L1+ TE showed an association with pathologic stage (P = .01), squamous differentiation (SqD) (P < .001), TILs by H&E (P = .02), PD-1+ peritumoral TILs (P = .01), and PD-L1+ peritumoral lymphohistiocytes (P = .002). Finally, there was a significant difference in PD-1+ peritumoral TILs in cases with SqD vs no SqD (P = .03). CONCLUSIONS Aggressive UTUC is associated with a distinct TM. Furthermore, TM of UTUC-SqD was distinctly different from those with no SqD, warranting study in a larger cohort.
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Affiliation(s)
- Aileen Grace P Arriola
- Department of Pathology and Laboratory Medicine, Temple University Hospital, Philadelphia, PA
| | - Sahar J Farahani
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Hersh K Bhargava
- Department of Molecular and Cell Biology, University of California, Berkeley
| | - Thomas J Guzzo
- Department of Urology, Hospital of the University of Pennsylvania, Philadelphia
| | - John S J Brooks
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Priti Lal
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
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17
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Wang HF, Wang SS, Tang YJ, Chen Y, Zheng M, Tang YL, Liang XH. The Double-Edged Sword-How Human Papillomaviruses Interact With Immunity in Head and Neck Cancer. Front Immunol 2019; 10:653. [PMID: 31001266 PMCID: PMC6454067 DOI: 10.3389/fimmu.2019.00653] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/11/2019] [Indexed: 02/05/2023] Open
Abstract
Patients with human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have remarkably better prognosis, which differs from HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) with respect to clinical, genomic, molecular, and immunological aspects, especially having the characteristics of high levels of immune cell infiltration and high degrees of immunosuppression. This review will summarize immune evasion mechanisms in HPV-positive HNSCC, analyze the host various immune responses to HPV and abundant numbers of infiltrating immune cell, and discuss the differences between HPV-positive HNSCC with cervical cancer. A deeper understanding of the immune landscape will help new concepts to emerge in immune-checkpoint oncology, which might be a valuable add-on to established concepts.
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Affiliation(s)
- Hao-Fan Wang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Sha-Sha Wang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Ya-Jie Tang
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan, China
| | - Yu Chen
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Min Zheng
- Department of Stomatology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
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18
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Malm IJ, Rooper LM, Bishop JA, Ozgursoy SK, Hillel AT, Akst LM, Best SR. Molecular and immunologic analysis of laryngeal squamous cell carcinoma in smokers and non-smokers. Am J Otolaryngol 2019; 40:213-217. [PMID: 30553600 DOI: 10.1016/j.amjoto.2018.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/05/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Laryngeal squamous cell carcinoma (LSCC) is strongly associated with tobacco use, but recent reports suggest an increasing incidence of LSCC in patients without traditional risk factors, suggesting an alternative etiology of tumorigenesis. The purpose of this study is to characterize this non-smoking population and to compare immunohistochemical markers in tumor specimens from non-smokers and smokers with LSCC. METHODS A retrospective chart review of patients with LSCC at Johns Hopkins Hospital (JHH) was performed. A tissue microarray (TMA) was constructed with tumor specimen from non-smokers with stage and age-matched smokers and stained for a variety of immunologic and molecular targets. RESULTS In the JHH cohort of 521 patients, 12% (n = 63) were non-smokers. Non-smokers were more likely to be <45 years old at time of diagnosis (OR 4.13, p = 0.001) and to have glottic tumors (OR 2.46, p = 0.003). The TMA was comprised of tumors from 34 patients (14 non-smokers, 20 smokers). Only 2 patients (6%) were human-papillomavirus (HPV) positive by high-risk RNA in situ hybridization (ISH). There was no correlation between smoking status and p16 (p = 0.36), HPV-ISH positivity (p = 0.79), phosphatase and tensin homolog (PTEN, p = 0.91), p53 (p = 0.14), or programmed death-ligand 1 (PD-L1, p = 0.27) expression. CONCLUSIONS Non-smokers with LSCC are more likely to be younger at the time of diagnosis and have glottic tumors than smokers with LSCC. In TMA analysis of stage and age-matched specimens from smoker and non-smokers with LSCC, the pattern of expression for common molecular and immunologic markers is similar. Further, HPV does not appear to be a major causative etiology of LSCC in either smokers or non-smokers in our cohort of patients.
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Affiliation(s)
- Ian-James Malm
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Lisa M Rooper
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Justin A Bishop
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA
| | | | - Alexander T Hillel
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Lee M Akst
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Simon R Best
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
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19
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Yang B, Liu T, Qu Y, Liu H, Zheng SG, Cheng B, Sun J. Progresses and Perspectives of Anti-PD-1/PD-L1 Antibody Therapy in Head and Neck Cancers. Front Oncol 2018; 8:563. [PMID: 30547012 PMCID: PMC6279860 DOI: 10.3389/fonc.2018.00563] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/12/2018] [Indexed: 12/14/2022] Open
Abstract
Head and neck cancer is the 6th most common malignancy worldwide and urgently requires novel therapy methods to change the situation of low 5-years survival rate and poor prognosis. Targeted therapy provides more precision, higher efficiency while lower adverse effects than traditional treatments like surgery, radiotherapy, and chemotherapy. Blockade of PD-1 pathway with antibodies against PD-1 or PD-L1 is such a typical targeted therapy which reconstitutes anti-tumor activity of T cell in treatments of cancers, especially those highly expressing PD-L1, including head and neck cancers. There are many clinical trials all over the world and FDA has approved anti-PD-1/PD-L1 drugs for head and neck cancers. However, with the time going, the dark side of this therapy has emerged, including some serious side effects and drug resistance. Novel materials like nanoparticles and combination therapy have been developed to improve the efficacy. At the same time, standards for evaluation of activity and safety are to be established for this new therapy. Here we provide a systematic review with comprehensive depth on the application of anti-PD1/PD-L1 antibodies in head and neck cancer treatment: mechanism, drugs, clinical studies, influencing factors, adverse effects and managements, and the potential future developments.
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Affiliation(s)
- Bo Yang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Tingjun Liu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yang Qu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Hangbo Liu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Song Guo Zheng
- Division of Rheumatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, United States
| | - Bin Cheng
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Jianbo Sun
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
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20
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Concha-Benavente F, Kansy B, Moskovitz J, Moy J, Chandran U, Ferris RL. PD-L1 Mediates Dysfunction in Activated PD-1 + NK Cells in Head and Neck Cancer Patients. Cancer Immunol Res 2018; 6:1548-1560. [PMID: 30282672 DOI: 10.1158/2326-6066.cir-18-0062] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 07/25/2018] [Accepted: 09/27/2018] [Indexed: 01/02/2023]
Abstract
Inhibitory immune-checkpoint receptors (ICRs), including programmed death 1 (PD-1), have been characterized as exhaustion markers on T cells that infiltrate the tumor microenvironment (TME) of many cancer types, including head and neck cancer (HNC). However, expression and function of ICRs, including PD-1, on natural killer (NK) cells remains less defined. NK cells are innate immune effector cells that lyse epidermal growth factor receptor-overexpressing HNC cells via cetuximab-mediated antibody-dependent cytotoxicity. Cetuximab is clinically effective but only in 10% to 15% of patients. Therefore, it is necessary to investigate how immunomodulation with cetuximab or PD-1 blockade might enhance NK cell responses in the TME and improve monoclonal antibody therapeutic efficacy. We observed that expression of PD-1 on NK cells marks an activated phenotype, which was suppressed only after binding programmed death ligand-1 (PD-L1). HNC patients who exhibit higher circulating PD-1+ NK cells associate with better clinical outcome, and these cells are enriched in the TME. Cetuximab-mediated NK cell activation increased PD-1 expression on NK cells in vitro, which was confirmed in vivo in a prospective neoadjuvant cetuximab trial. In contrast, PD-L1 ligation of PD-1+ NK cells diminished their activation status, whereas PD-1 blockade increased cetuximab-mediated NK cell activation and cytotoxicity, but only against HNC targets with high PD-L1 expression. Therefore, blocking the PD-1-PD-L1 axis may be a useful strategy to reverse immune evasion of HNC tumors with high PD-L1 expression during cetuximab therapy by reversing NK cell dysfunction.
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Affiliation(s)
- Fernando Concha-Benavente
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
- University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Benjamin Kansy
- Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Jessica Moskovitz
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jennifer Moy
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Uma Chandran
- Department of Biomedical informatics, University of Pittsburgh, Pennsylvania
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
- University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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21
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Ward FJ, Dahal LN, Abu-Eid R. On the Road to Immunotherapy-Prospects for Treating Head and Neck Cancers With Checkpoint Inhibitor Antibodies. Front Immunol 2018; 9:2182. [PMID: 30319637 PMCID: PMC6165864 DOI: 10.3389/fimmu.2018.02182] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 09/04/2018] [Indexed: 12/23/2022] Open
Abstract
Head and neck cancers (HNC) represent a heterogeneous cluster of aggressive malignancies that account for 3% of all cancer cases in the UK. HNC is increasing in frequency particularly in the developing world, which is related to changes in risk factors. Unfortunately, the mortality rate is high, which is chiefly attributed to late diagnosis at stages where traditional treatments fail. Cancer immunotherapy has achieved great successes in anti-tumor therapy. Checkpoint inhibitor (CI) antibodies enhance anti-tumor activity by blocking inhibitory receptors to drive tumor-specific T and NK cell effector responses. Since their introduction in 2011, CI antibodies have been approved for many cancer types including HNC. Here, we examine the development of CI therapies and look forward to future developments for treatment of HNC with CI therapies.
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Affiliation(s)
- Frank J Ward
- Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
| | - Lekh N Dahal
- Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Rasha Abu-Eid
- Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.,Institute of Dentistry, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
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22
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Deng WW, Wu L, Sun ZJ. Co-inhibitory immune checkpoints in head and neck squamous cell carcinoma. Oral Dis 2018; 24:120-123. [PMID: 29480599 DOI: 10.1111/odi.12746] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 08/17/2017] [Accepted: 08/17/2017] [Indexed: 12/28/2022]
Abstract
The upregulation of co-inhibitory immune checkpoints hampers the immune response toward tumor cells and facilitates the tumor cells ability to evade immunosurveillance. Specific inhibitory immune checkpoint delivers inhibitory signals to T cells using multiple mechanisms. More in-depth understanding of the co-inhibitory immune checkpoints could be exploited for head and neck squamous cell carcinoma (HNSCC) treatment. In this review, we summarize the expression and the mechanism of partial co-inhibitory immune checkpoint signals and discuss targeting co-inhibitory immune checkpoints as an immunotherapeutic target for cancer therapy. This review may provide a better understanding of the co-inhibitory immune checkpoints and could promote applications of immunotherapy.
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Affiliation(s)
- W-W Deng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - L Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Z-J Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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23
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Amoils M, Kim J, Lee C, Sunwoo JB, Colevas AD, Aasi SZ, Hollmig ST, Ma Y, Divi V. PD-L1 Expression and Tumor-Infiltrating Lymphocytes in High-Risk and Metastatic Cutaneous Squamous Cell Carcinoma. Otolaryngol Head Neck Surg 2018; 160:93-99. [PMID: 30012051 DOI: 10.1177/0194599818788057] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To characterize programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) positivity for locally aggressive or regionally metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC). STUDY DESIGN Retrospective chart review, followed by immunohistochemical staining of archived tumor specimens. SETTING Tertiary academic medical center. SUBJECTS AND METHODS After identification of 101 patients treated surgically for locally advanced or regionally metastatic cHNSCC, archived tissue was stained and graded for PD-L1 expression in addition to TIL presence. Cross-tabulation was performed to examine the association between either of these variables and clinicopathologic features and outcomes. RESULTS A total of 101 patients met inclusion criteria, but archived tissue was available only for 83 (31 primaries, 52 metastases). The majority of primary tumors demonstrated grade 1 PD-L1 staining, while grade 2 staining was more likely for metastases. Neither high- nor low-grade PD-L1 expression correlated with any clinicopathologic variable for primary tumors. However, for metastases, high-grade staining was significantly associated with regional recurrence (15 of 19, P = .02). TILs were present for 65% of primary tumors and 90% of regional metastases but did not correlate with any clinicopathologic variables. CONCLUSION Diffuse expression of PD-L1 in this study highlights the possibility of using immunotherapy in the form of programmed death 1/PD-L1 blockade to improve treatment for this devastating disease. However, further studies are needed to clarify the significance of PD-L1 expression and TIL positivity for locally advanced or regionally metastatic cHNSCC.
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Affiliation(s)
- Misha Amoils
- 1 Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California, USA
| | - Jinah Kim
- 2 Department of Dermatology, Stanford University, Stanford, California, USA
| | - Carolyn Lee
- 2 Department of Dermatology, Stanford University, Stanford, California, USA
| | - John B Sunwoo
- 1 Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California, USA
| | - A Dimitrios Colevas
- 3 Division of Oncology, Stanford Department of Medicine, Stanford Cancer Center, Stanford University, Stanford, California, USA
| | - Sumaira Z Aasi
- 2 Department of Dermatology, Stanford University, Stanford, California, USA
| | - S Tyler Hollmig
- 2 Department of Dermatology, Stanford University, Stanford, California, USA
| | - Yifei Ma
- 1 Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California, USA
| | - Vasu Divi
- 1 Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California, USA
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24
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Schneider S, Kadletz L, Wiebringhaus R, Kenner L, Selzer E, Füreder T, Rajky O, Berghoff AS, Preusser M, Heiduschka G. PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis - impact on clinical outcome. Histopathology 2018; 73:573-584. [PMID: 29742291 DOI: 10.1111/his.13646] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 04/24/2018] [Accepted: 05/04/2018] [Indexed: 12/29/2022]
Abstract
AIMS Expression profiles and clinical impact of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) are not elucidated fully. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and the impact on patients' clinical outcome. METHODS AND RESULTS Immunohistochemical staining patterns of PD-L1 and PD-1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated with patients' clinical data. PD-L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis, and correlates significantly with decreased overall survival (OS) (P = 0.01) and disease-free survival (DFS) (P = 0.001) in oral cavity squamous cell carcinoma patients. PD-L1 expression was associated with presence of lymph node metastasis (P = 0.0223). Infiltration of PD-1-expressing lymphocytes correlates significantly with favourable OS (P = 0.001) and DFS (P = 0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (P = 0.007) and DFS (P = 0.001). Presence of PD-1 TILs also correlates significantly with better OS (P = 0.005) and DFS (P = 0) in the human papilloma virus (HPV)-negative cohort. Cox regression multivariate analysis revealed PD-1 TIL expression as an independent prognostic marker for OS (P = 0.004) and DFS (P = 0.001) and T stage was validated as negative prognostic marker for OS (P = 0.011). PD-1-expressing lymphocytes (P = 0.0412) and PD-L1 expression (P = 0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases. CONCLUSIONS Our results characterise the expression profiles of PD-1 axis proteins in HNSCC which might serve as possible clinical prognostic markers.
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Affiliation(s)
- Sven Schneider
- Department of Otorhinolaryngology, Head and Neck Surgery, Vienna, Austria
| | - Lorenz Kadletz
- Department of Otorhinolaryngology, Head and Neck Surgery, Vienna, Austria
| | - Robert Wiebringhaus
- Department of Experimental Pathology and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Department of Experimental Pathology and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria.,Department of Laboratory Animal Pathology, University of Veterinary Medicine of Vienna, Vienna, Austria.,Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | | | - Thorsten Füreder
- Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Orsolya Rajky
- Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Anna S Berghoff
- Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Matthias Preusser
- Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Gregor Heiduschka
- Department of Otorhinolaryngology, Head and Neck Surgery, Vienna, Austria
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25
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Schoenfeld JD, Gjini E, Rodig SJ, Tishler RB, Rawal B, Catalano PJ, Uppaluri R, Haddad RI, Hanna GJ, Chau NG, Rabinowits G, Lorch J, Jo VY, Krane JF, Goguen LA, Annino DJ, Abdelrahman S, Lipschitz M, Margalit DN. Evaluating the PD-1 Axis and Immune Effector Cell Infiltration in Oropharyngeal Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys 2018; 102:137-145. [PMID: 29960819 DOI: 10.1016/j.ijrobp.2018.05.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 03/27/2018] [Accepted: 05/01/2018] [Indexed: 10/28/2022]
Abstract
PURPOSE Programmed death-1 (PD-1) inhibitors are approved for the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Ongoing and planned randomized phase 3 trials are testing the benefit of combining PD-1/programmed death-ligand 1 (PD-L1) inhibitors with chemoradiation for patients with locoregionally confined SCCHN. Few studies have investigated relationships among potential predictive pathologic biomarkers such as PD-L1, PD-L2, and PD-1 in this population and associations between these markers and clinical characteristics. METHODS AND MATERIALS We retrospectively reviewed records and pathology from 81 patients with locoregional oropharynx SCCHN treated with curative intent. Samples were analyzed for PD-L1, PD-L2, PD-1, CD8, and CD56 expression using immunohistochemistry. Human papilloma virus (HPV) status was determined by p16-immunohistochemistry and confirmed by in situ hybridization or polymerase chain reaction-based HPV typing. Correlations between HPV status, clinical features, and recurrence status with immune markers in both tumor and tumor-associated stroma were determined. Hazard ratios were estimated via Cox proportional hazards model. RESULTS Tumor PD-L1 expression was inversely associated with age (P = .01) and the highest levels of expression (>30% of tumor cells) were observed in HPV-associated tumors. There was a correlation between tumor and stromal PD-L1 expression (P = < .0001). PD-1 and CD8 expression within tumor deposits was associated with HPV status (P = 0.003 and P = .008, respectively) and decreased local recurrence (P = .001 and P < .001, respectively). In addition to the association between tumor and stromal PD-1 (P < .0001), PD-1 was also correlated with tumor PD-L1 expression (P < .001). CD56+ natural killer cell infiltrates correlated with PD-L1 expression. CONCLUSIONS In patients with untreated oropharyngeal SCCHN, HPV-associated tumors displayed the highest levels of PD-L1 expression and PD-1+ and CD8+ immune cells. Locally recurrent tumors had lower levels of PD-L1, PD-1, and CD-8 positivity. Whereas almost all SCCHN tumors had CD56+ infiltrating natural killer cells, most tumors didn't have PD-L2 expression. These associations may help predict which patients may benefit most from immunotherapeutic approaches.
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Affiliation(s)
- Jonathan D Schoenfeld
- Department of Radiation Oncology, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Evisa Gjini
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Scott J Rodig
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Roy B Tishler
- Department of Radiation Oncology, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bhupendra Rawal
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Paul J Catalano
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ravindra Uppaluri
- Division of Otolaryngology, Department of Surgery, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Robert I Haddad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Glenn J Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Nicole G Chau
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Guilherme Rabinowits
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jochen Lorch
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Vickie Y Jo
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Jeffrey F Krane
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Laura A Goguen
- Division of Otolaryngology, Department of Surgery, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Donald J Annino
- Division of Otolaryngology, Department of Surgery, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sara Abdelrahman
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mikel Lipschitz
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Danielle N Margalit
- Department of Radiation Oncology, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts
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26
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Zhang P, Liu J, Li W, Li S, Han X. Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD-L1. Cancer Med 2018; 7:3178-3187. [PMID: 29761938 PMCID: PMC6051176 DOI: 10.1002/cam4.1529] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 03/06/2018] [Accepted: 04/09/2018] [Indexed: 12/11/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death‐ligand 1 (PD‐L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD‐L1 was verified from HNSCC samples at local hospital with immunohistochemistry. PD‐L1 expression in the acquired cisplatin‐resistant HNSCC cells was examined by PCR and WB in order to test PD‐L1‐induced chemoresistance. LfcinB inoculation in cisplatin‐resistant HNSCC cells and in the nude mice was introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism. High CD274 mRNA (>125 FPKM) from TCGA database had a significantly reduced 5‐year survival rate, and a lower 5‐year survival rate in the chemotherapy and radiotherapy‐treated patients (P < .05). PD‐L1 overexpression was further supported from analysis of 40 HNSCC specimens. PD‐L1 and IL‐6 in the established cisplatin‐resistant HNSCC cells were shown significantly higher (P < .05). IL‐6 and PD‐L1 expression were partially inhibited by the anti‐IL‐6/STAT3 antibody. LfcinB displayed a direct cytotoxic effect on cisplatin‐resistant HNSCC cells and HNSCC xenografts of cisplatin‐resistant cells in the nude mice displayed significant reduction in tumor volume after LfcinB injection (P < .05). Besides, the increase of IL‐6 and PD‐L1 in cisplatin‐resistant HNSCC cells was abolished in vitro by LfcinB (P < .05). PD‐L1 expression in HNSCC cells correlates with poor prognosis and chemoresistance, and LfcinB might provide therapeutic potential in HNSCC patients through modulating IL‐6 and PD‐L1.
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Affiliation(s)
- Pei Zhang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinzhong Liu
- Key Laboratory of Tumor Pathology, Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenlu Li
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shanshan Li
- Key Laboratory of Tumor Pathology, Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinguang Han
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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27
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Brogden KA, Parashar D, Hallier AR, Braun T, Qian F, Rizvi NA, Bossler AD, Milhem MM, Chan TA, Abbasi T, Vali S. Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy. BMC Cancer 2018; 18:225. [PMID: 29486723 PMCID: PMC5897943 DOI: 10.1186/s12885-018-4134-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 02/15/2018] [Indexed: 12/21/2022] Open
Abstract
Background Programmed Death Ligand 1 (PD-L1) is a co-stimulatory and immune checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a hallmark of adaptive resistance and its expression is often used to predict the outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However, clinical benefits do not occur in all patients and new approaches are needed to assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we hypothesized that patient tumor cell genomics influenced cell signaling and expression of PD-L1, chemokines, and immunosuppressive molecules and these profiles could be used to predict patient clinical responses. Methods We used a recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene mutational profiles in patient exomes were identified and annotated into a cancer network to create NSCLC patient-specific predictive computational simulation models. Validation checks were performed on the cancer network, simulation model predictions, and PD-1 match rates between patient-specific predicted and clinical responses. Results Expression profiles of these 24 chemokines and immunosuppressive molecules were used to identify patients who would or would not respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to predict which patients would or would not respond to PD-1 immunotherapy. Adding chemokine and immunosuppressive molecule expression profiles allowed patient models to achieve a greater than 85.0% predictive correlation among predicted and reported patient clinical responses. Conclusions Our results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies. Electronic supplementary material The online version of this article (10.1186/s12885-018-4134-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kim A Brogden
- Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, 801 Newton Road, Iowa City, IA, 52242, USA.
| | - Deepak Parashar
- Cellworks Research India Ltd., Whitefield, Bangalore, 560066, India
| | - Andrea R Hallier
- Biomedical Engineering, The University of Iowa, 5318 SC, Iowa City, IA, 52242, USA
| | - Terry Braun
- Biomedical Engineering, The University of Iowa, 5318 SC, Iowa City, IA, 52242, USA
| | - Fang Qian
- Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, 801 Newton Road, Iowa City, IA, 52242, USA.,Division of Biostatistics and Research Design, College of Dentistry, The University of Iowa, 801 Newton Road, Iowa City, IA, 52242, USA
| | - Naiyer A Rizvi
- Division of Hematology/Oncology, Columbia University Medical Center, 177 Fort Washington Avenue, New York, NY, 10032, USA
| | - Aaron D Bossler
- Molecular Pathology Laboratory, Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., C606GH, Iowa City, IA, 52242, USA
| | - Mohammed M Milhem
- Clinical Services, Experimental Therapeutics, Melanoma and Sarcoma Program, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, 52242, USA
| | - Timothy A Chan
- Department of Radiation Oncology, Human Oncology and Pathogenesis Program, Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Taher Abbasi
- Cellworks Group, Inc., 2033 Gateway Place Suite 500, San Jose, CA, 95110, USA
| | - Shireen Vali
- Cellworks Group, Inc., 2033 Gateway Place Suite 500, San Jose, CA, 95110, USA
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28
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Taube JM, Galon J, Sholl LM, Rodig SJ, Cottrell TR, Giraldo NA, Baras AS, Patel SS, Anders RA, Rimm DL, Cimino-Mathews A. Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol 2018; 31:214-234. [PMID: 29192647 PMCID: PMC6132263 DOI: 10.1038/modpathol.2017.156] [Citation(s) in RCA: 266] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/06/2017] [Accepted: 09/24/2017] [Indexed: 02/06/2023]
Abstract
Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an 'Immunoscore', which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.
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Affiliation(s)
- Janis M Taube
- Department of Dermatology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche des Cordeliers, Paris, France
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Scott J Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Tricia R Cottrell
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Nicolas A Giraldo
- Department of Dermatology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Alexander S Baras
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Sanjay S Patel
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Robert A Anders
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Ashley Cimino-Mathews
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
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29
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Cutaneous squamous cell carcinoma. J Am Acad Dermatol 2018; 78:249-261. [DOI: 10.1016/j.jaad.2017.08.058] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 07/23/2017] [Accepted: 08/17/2017] [Indexed: 11/19/2022]
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30
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Straub M, Drecoll E, Pfarr N, Weichert W, Langer R, Hapfelmeier A, Götz C, Wolff KD, Kolk A, Specht K. CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity. Oncotarget 2017; 7:12024-34. [PMID: 26918453 PMCID: PMC4914266 DOI: 10.18632/oncotarget.7593] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 01/30/2016] [Indexed: 01/07/2023] Open
Abstract
Immunomodulatory therapies, targeting the immune checkpoint receptor-ligand complex PD-1/PD-L1 have shown promising results in early phase clinical trials in solid malignancies, including carcinomas of the head and neck. In this context, PD-L1 protein expression has been proposed as a potentially valuable predictive marker. In the present study, expression of PD-L1 and PD-1 was evaluated by immunohistochemistry in 80 patients with predominantly HPV-negative oral squamous cell carcinomas and associated nodal metastasis. In addition, CD274/PD-L1 gene copy number status was assessed by fluorescence in situ hybridization analysis. PD-L1 expression was detected in 36/80 (45%) cases and concordance of PD-L1 expression in primary tumor and corresponding nodal metastasis was present in only 20/28 (72%) cases. PD-1 expression was found in tumor-infiltrating lymphocytes (TILs) but not in tumor cells. CD274/PD-L1 gene amplification was detected in 19% of cases, with high level PD-L1 amplification present in 12/80 (15%), and low level amplification in 3/80 (4%). Interestingly, CD274/PD-L1 gene amplification was associated with positive PD-L1 immunostaining in only 73% of cases. PD-L1 copy number status was concordant in primary tumor and associated metastases. Clinically, PD-L1 tumor immunopositivity was associated with a higher risk for nodal metastasis at diagnosis, overall tumor related death und recurrence. Based on our findings we propose to include PD-L1 copy number status in addition to protein status in screening programs for future clinical trials with immunotherapeutic strategies targeting the PD-1/PD-L1 axis.
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Affiliation(s)
- Melanie Straub
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Enken Drecoll
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Nicole Pfarr
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich, Munich, Germany.,National Center of Tumor Diseases (NCT), Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Rupert Langer
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Alexander Hapfelmeier
- Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany
| | - Carolin Götz
- Department of Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Klaus-Dietrich Wolff
- Department of Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Andreas Kolk
- Department of Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Katja Specht
- Institute of Pathology, Technical University of Munich, Munich, Germany
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31
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Qi X, Jia B, Zhao X, Yu D. Advances in T-cell checkpoint immunotherapy for head and neck squamous cell carcinoma. Onco Targets Ther 2017; 10:5745-5754. [PMID: 29238207 PMCID: PMC5716310 DOI: 10.2147/ott.s148182] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) has been found to be a complex group of malignancies characterized by their profound immunosuppression and high aggressiveness. In most cases of advanced HNSCC, treatment fails to obtain total cancer cure. Efforts are needed to develop new therapeutic approaches to improve HNSCC outcomes. In this light, T-cells "immune checkpoint" has attracted much attention in cancer immunotherapy. It has been broadly accepted that inhibitory T-cell immune checkpoints contribute to tumor immune escape through negative immune regulatory signals (cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], B7-H3, and B7-H4, etc). Current data suggest that PD-1 and CTLA-4 receptors can inhibit T-cell receptors and T-cell proliferation. Blockade of PD-1/PD-L1 and/or CTLA-4/CD28 pathways has shown promising tumor outcomes in clinical trials for advanced solid tumors like melanoma, renal cell cancer, and non-small cell lung cancer. The present review attempts to explore what is known about PD-1/PD-L1 and CTLA-4/CD28 pathways with a focus on HNSCC. We further discuss how these pathways can be manipulated with therapeutic intent.
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Affiliation(s)
- Xinmeng Qi
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital, Jilin University, Changchun, Jilin
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University
| | - Bo Jia
- Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing People’s Republic of China
| | - Xue Zhao
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital, Jilin University, Changchun, Jilin
| | - Dan Yu
- Department of Otolaryngology Head and Neck Surgery, The Second Hospital, Jilin University, Changchun, Jilin
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Beyond the Percentages of PD-L1-Positive Tumor Cells: Induced Versus Constitutive PD-L1 Expression in Primary and Metastatic Head and Neck Squamous Cell Carcinoma. Head Neck Pathol 2017; 12:221-229. [PMID: 28948509 PMCID: PMC5953879 DOI: 10.1007/s12105-017-0857-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 09/18/2017] [Indexed: 10/18/2022]
Abstract
Anti-PD1 antibody has been approved for metastatic squamous cell carcinoma of the head and neck (SCCHN) and objective response rates of approximately 20% have been reported. Defining PD-L1 expression at ≥ 1% tumor cells as positive, PD-L1-positive tumors showed a higher response rate. However, it is unclear whether 1% is the optimal cutoff, and studies on lung cancer suggested 50% cutoff as a stronger predictive biomarker. 96 primary SCCHN from oropharynx and oral cavity and 34 corresponding metastatic lesions were typed for membranous PD-L1 expression. p16 immunohistochemistry was used as a surrogate marker for HPV status in SCCHN from the oropharynx. Fifty-two of 96 (54%) tumors were PD-L1-positive, 72% if PD-L1 expression in tumor-infiltrating immunocytes was also included as positive. Fifteen of 34 primary-metastasis tumor pairs differed in PD-L1 expression, and p16(+) cases more frequently showed PD-L1 expression in immunocytes than p16(-) cases (82 vs. 45%, p < 0.05). PD-L1-positive SCCHN showed two distinct patterns of expression. In the induced pattern of expression, PD-L1-positive tumor cells were limited to the periphery of tumor nests at the tumor-immunocyte interface, comprising < 5% of tumor cells, and were almost always associated with PD-L1-positive immunocytes. In contrast, tumors with constitutive PD-L1 expression had a higher percentage of positive tumor cells, often diffusely distributed throughout the tumor, and often were not accompanied by PD-L1-positive immunocytes. We propose that distinguishing these two biologically distinctive patterns of PD-L1 expression and typing metastatic instead of primary lesions might better predict immunotherapeutic response to anti-PD1/PD-L1 regimens beyond just the percentage of PD-L1-positive tumor cells.
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Abstract
OPINION STATEMENT The survival rate for patients with advanced stages of squamous cell carcinoma of the head and neck (SCCHN) remains poor despite multimodal treatment options. Cetuximab, an anti-EGFR inhibitor, is the only FDA-approved targeted agent for this disease. Recent findings have implicated modifications of the microenvironment and, consequently, phenotypical modifications of the cancer cell, in treatment resistance mechanisms. For many years, cancer research has focused mainly on targetable sites on or inside the cancer cell. Nowadays, in preclinical and clinical studies, a greater emphasis is being placed on drugs that target the tumor microenvironment. Potential targets relate to tumor vascularization, immunology, extracellular matrix components, or cancer-associated fibroblasts. The combination of these new agents with standard treatment options is of particular interest to overcome resistance mechanisms and/or to increase treatment efficacy. Whereas antiangiogenic agents show poor clinical activity, immunotherapy seems to be a more promising tool with an objective response rate (ORR) of 20 % in patients with recurrent and/or metastatic squamous cell carcinoma (R/M SCC). Other targets, located inside the extracellular matrix or on cancer associated fibroblasts, are under preclinical investigation. These new agents all need to be tested in clinical trials alone, or in combination with standard treatment modalities, based on preclinical data. To increase our knowledge of the complex network between the cancer cell and its environment, preclinical studies should consider co-culture models, and clinical studies should incorporate a translational research objective.
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Lechner A, Schlößer H, Rothschild SI, Thelen M, Reuter S, Zentis P, Shimabukuro-Vornhagen A, Theurich S, Wennhold K, Garcia-Marquez M, Tharun L, Quaas A, Schauss A, Isensee J, Hucho T, Huebbers C, von Bergwelt-Baildon M, Beutner D. Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget 2017; 8:44418-44433. [PMID: 28574843 PMCID: PMC5546490 DOI: 10.18632/oncotarget.17901] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 04/25/2017] [Indexed: 01/10/2023] Open
Abstract
The composition of tumor-infiltrating lymphocytes (TIL) reflects biology and immunogenicity of cancer. Here, we characterize T-cell subsets and expression of immune checkpoint molecules in head and neck squamous cell carcinoma (HNSCC). We analyzed TIL subsets in primary tumors (n = 34), blood (peripheral blood mononuclear cells (PBMC); n = 34) and non-cancerous mucosa (n = 7) of 34 treatment-naïve HNSCC patients and PBMC of 15 healthy controls. Flow cytometry analyses revealed a highly variable T-cell infiltration mainly of an effector memory phenotype (CD45RA-/CCR7-). Naïve T cells (CD45RA+/CCR7+) were decreased in the microenvironment compared to PBMC of patients, while regulatory T cells (CD4+/CD25+/CD127low and CD4+/CD39+) were elevated. Furthermore, we performed digital image analyses of entire cross sections of HNSCC to define the 'Immunoscore' (CD3+ and CD8+ cell infiltration in tumor core and invasive margin) and quantified MHC class I expression on tumor cells by immunohistochemistry. Immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) were increased in TILs compared to peripheral T cells in flow-cytometric analysis. Human papillomavirus (HPV) positive tumors showed higher numbers of TILs, but a similar composition of T-cell subsets and checkpoint molecule expression compared to HPV negative tumors. Taken together, the tumor microenvironment of HNSCC is characterized by a strong infiltration of regulatory T cells and high checkpoint molecule expression on T-cell subsets. In view of increasingly used immunotherapies, a detailed knowledge of TILs and checkpoint molecule expression on TILs is of high translational relevance.
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Affiliation(s)
- Axel Lechner
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany
| | - Hans Schlößer
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Sacha I. Rothschild
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- University Hospital Basel, Department of Internal Medicine, Medical Oncology, Basel, Switzerland
| | - Martin Thelen
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Sabrina Reuter
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Peter Zentis
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Alexander Shimabukuro-Vornhagen
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
| | - Sebastian Theurich
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
- Max-Planck-Institute for Metabolism Research, Cologne, Germany
| | - Kerstin Wennhold
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Maria Garcia-Marquez
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Lars Tharun
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Astrid Schauss
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Jörg Isensee
- Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, University of Cologne, Germany
| | - Tim Hucho
- Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, University of Cologne, Germany
| | - Christian Huebbers
- Jean-Uhrmacher Institute for Clinical ENT Research, University of Cologne, Cologne, Germany
| | - Michael von Bergwelt-Baildon
- Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
| | - Dirk Beutner
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany
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Xie X, O'Neill W, Pan Q. Immunotherapy for head and neck cancer: the future of treatment? Expert Opin Biol Ther 2017; 17:701-708. [PMID: 28368668 DOI: 10.1080/14712598.2017.1315100] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with >500,000 cases diagnosed each year. HNSCC patients often present to the clinic with advanced disease and are managed with a multi-disciplinary approach consisting of surgery, chemotherapy, and/or radiation. Morbidity and quality of life issues are major challenges in this patient population due to the debilitating effects of standard of care treatment paradigms. There is a critical need for new therapeutic approaches to manage HNSCC with better anti-tumor activities and toxicity profiles. Immunotherapy has gained traction as a precision medicine initiative to manage solid malignancies. Areas covered: The authors review current knowledge of immune escape mechanisms and discuss key immunotherapies in HNSCC with an emphasis on clinical trials data. Expert opinion: The excitement over the potential of immunotherapy to manage solid malignancies, including HNSCC is high and warranted based on the impressive clinical data accrued to date. Research in immunity and immune modulation in cancer has been invigorated and offers the potential to reveal novel vulnerabilities that may be exploitable pharmacologically. The evolution of immunotherapy will continue and move toward rational combinations with other immunotherapies or molecularly-targeted agents in the first-line, adjuvant, and recurrent/metastatic settings in HNSCC.
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Affiliation(s)
- Xiujie Xie
- a Department of Otolaryngology-Head and Neck Surgery , The Ohio State University Wexner Medical Center, The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA
| | - Wendi O'Neill
- a Department of Otolaryngology-Head and Neck Surgery , The Ohio State University Wexner Medical Center, The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA
| | - Quintin Pan
- b Department of Otolaryngology-Head and Neck Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA.,c Translational Therapeutics Program , The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA
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Levingston CA, Young MRI. Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD-1 antibodies. Int J Cancer 2017; 140:1609-1619. [PMID: 27914100 PMCID: PMC5324681 DOI: 10.1002/ijc.30543] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 11/10/2016] [Accepted: 11/16/2016] [Indexed: 12/26/2022]
Abstract
A carcinogen-induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD-1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL-2 and the inflammatory cytokines IL-6, IL-17 and TNF-α by spleen cells of lesion-bearing mice that were treated with PD-1 antibody for 1 week compared to cytokine production by spleen cells of lesion-bearing mice treated with control antibody. Production of IFN-γ increased at 3 weeks of PD-1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD-1 antibody-treated mice. Flow cytometric analysis for IFN-γ-expressing cells showed shifts in CD4+ cells expressing IFN-γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD-1 antibody-treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD-1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD-1 antibody-treated mice progressed to the same degree as in control antibody-treated mice. Overall, these results show an early beneficial response to PD-1 antibody treatment, which then fails with continued treatment and lesion progression.
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Affiliation(s)
| | - M Rita I Young
- Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC.,Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
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Is There Evidence for the Presence and Relevance of the PD-1/PD-L1 Pathway in Oral Squamous Cell Carcinoma? Hints From an Immunohistochemical Study. J Oral Maxillofac Surg 2016; 75:969-977. [PMID: 27916470 DOI: 10.1016/j.joms.2016.11.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 11/05/2016] [Indexed: 12/31/2022]
Abstract
PURPOSE To examine oral squamous cell carcinoma (OSCC) specimens for programmed death ligand-1 (PD-L1) expression and presence of programmed death-1 (PD-1)-positive tumor-infiltrating lymphocytes (TILs) and to determine possible clinicopathologic implications. It was hypothesized that PD-L1 expression and PD-1-positive TIL presence in OSCC would have no clinical relevance. MATERIALS AND METHODS The authors implemented a retrospective cohort study design. The study cohort was chosen in compliance with predefined inclusion criteria. Demographic, clinical, and histopathologic data were gathered. Tissue microarrays were obtained from paraffin-embedded OSCC specimens and analyzed immunohistochemically for PD-L1 expression and PD-1-positive TIL infiltration. PD-L1 positivity of OSCC specimens served as the predictor variable and neck node metastasis served as the primary outcome variable. Descriptive and inferential statistics were computed and the significance level was set at a P value less than or equal to .05. RESULTS The study sample was composed of 88 patients (48 men, 40 women; mean age, 61.34 yr). Marked PD-L1 expression was detected in 29% of OSCC specimens (26 of 88) and 83% of specimens (73 of 88) exhibited a high rate of PD-1-positive TIL infiltration. PD-L1 positivity of OSCC samples was significantly associated with the anatomic origin of OSCC (P = .039), presence of cervical metastasis (P = .039), and high PD-L1-positive TIL infiltration (P = .033). CONCLUSION A considerable proportion of OSCCs exhibited marked PD-L1 expression. This could be associated with clinical parameters. PD-L1 expression in OSCC might differ depending on its anatomic origin. PD-1-positive TILs could be detected in most OSCC specimens. These findings might indicate a potential role for the PD-1 and PD-L1 pathway in OSCC.
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Rancoule C, Vallard A, Espenel S, Guy JB, Xia Y, El Meddeb Hamrouni A, Rodriguez-Lafrasse C, Chargari C, Deutsch E, Magné N. Immunotherapy in head and neck cancer: Harnessing profit on a system disruption. Oral Oncol 2016; 62:153-162. [DOI: 10.1016/j.oraloncology.2016.09.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/26/2016] [Accepted: 09/04/2016] [Indexed: 12/25/2022]
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Latteyer S, Tiedje V, Schilling B, Führer D. Perspectives for immunotherapy in endocrine cancer. Endocr Relat Cancer 2016; 23:R469-84. [PMID: 27485460 DOI: 10.1530/erc-16-0169] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 08/02/2016] [Indexed: 12/16/2022]
Abstract
The fight against cancer has seen major breakthroughs in recent years. More than a decade ago, tyrosine kinase inhibitors targeting constitutively activated signaling cascades within the tumor inaugurated a new era of oncological therapy. Recently, immunotherapy with immune checkpoint inhibitors has started to revolutionize the treatment of several malignancies, most notably malignant melanoma, leading to the renaissance and the long-awaited breakthrough of immunooncology. This review provides an overview of the basis of immunotherapy from its initial concepts of anti-tumor immunity and cell-based therapy to the development of immune checkpoint inhibitors and discusses published studies and the perspectives of immunooncology for the treatment of endocrine malignancies.
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Affiliation(s)
- S Latteyer
- Department of Endocrinology and MetabolismUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany Endocrine Tumour Center at West German Cancer Center (WTZ)Essen, Germany
| | - V Tiedje
- Department of Endocrinology and MetabolismUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany Endocrine Tumour Center at West German Cancer Center (WTZ)Essen, Germany
| | - B Schilling
- Department of DermatologyVenereology and Allergology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany German Cancer Consortium (DKTK)Heidelberg, Germany
| | - D Führer
- Department of Endocrinology and MetabolismUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany Endocrine Tumour Center at West German Cancer Center (WTZ)Essen, Germany
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40
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Yu GT, Bu LL, Huang CF, Zhang WF, Chen WJ, Gutkind JS, Kulkarni AB, Sun ZJ. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma. Oncotarget 2016; 6:42067-80. [PMID: 26573233 PMCID: PMC4747210 DOI: 10.18632/oncotarget.5955] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/26/2015] [Indexed: 12/15/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) play key roles in the tumor immune suppressive network and tumor progression. However, precise roles of programmed death-1 (PD-1) in immunological functions of MDSCs and TAMs in head and neck squamous cell carcinoma (HNSCC) have not been clearly elucidated. In the present study, we show that PD-1 and PD-L1 levels were significantly higher in human HNSCC specimen than in normal oral mucosa. MDSCs and TAMs were characterized in mice and human HNSCC specimen, correlated well with PD-1 and PD-L1 expression. αPD-1 treatment was well tolerated and significantly reduced tumor growth in the HNSCC mouse model along with significant reduction in MDSCs and TAMs in immune organs and tumors. Molecular analysis suggests a reduction in the CD47/SIRPα pathway by PD-1 blockade, which regulates MDSCs, TAMs, dendritic cell as well as effector T cells. Hence, these data identify that PD-1/PD-L1 axis is significantly increased in human and mouse HNSCC. Adoptive αPD-1 immunotherapy may provide a novel therapeutic approach to modulate the micro- and macro- environment in HNSCC.
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Affiliation(s)
- Guang-Tao Yu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan University, Wuhan, China
| | - Lin-Lin Bu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan University, Wuhan, China
| | - Cong-Fa Huang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan University, Wuhan, China
| | - Wen-Feng Zhang
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wan-Jun Chen
- Oral and Pharyngeal Cancer Branch, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - J Silvio Gutkind
- Oral and Pharyngeal Cancer Branch, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Ashok B Kulkarni
- Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan University, Wuhan, China.,Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.,Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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Mallen-St Clair J, Alani M, Wang MB, Srivatsan ES. Human papillomavirus in oropharyngeal cancer: The changing face of a disease. Biochim Biophys Acta Rev Cancer 2016; 1866:141-150. [PMID: 27487173 DOI: 10.1016/j.bbcan.2016.07.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/14/2016] [Accepted: 07/29/2016] [Indexed: 12/18/2022]
Abstract
The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease.
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Affiliation(s)
- Jon Mallen-St Clair
- Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Mustafa Alani
- UCLA School of Dentistry, Los Angeles, CA, United States
| | - Marilene B Wang
- Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System/David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Member of Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, United States
| | - Eri S Srivatsan
- Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System/David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Member of Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, United States.
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Johnson SD, Levingston C, Young MRI. Premalignant Oral Lesion Cells Elicit Increased Cytokine Production and Activation of T-cells. Anticancer Res 2016; 36:3261-70. [PMID: 27354582 PMCID: PMC5032137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 06/09/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND Head and neck squamous cell carcinomas (HNSCC) are known to evade the host immune response. How premalignant oral lesions modulate the immune response, however, has yet to be elucidated. MATERIALS AND METHODS A mouse model of oral carcinogenesis was used to determine how mediators from premalignant oral lesion cells vs. HNSCC cells impact on immune cytokine production and activation. RESULTS Media conditioned by premalignant lesion cells elicited an increased production of T cell-associated cytokines and proinflammatory mediators from cervical lymph node cells compared to media conditioned by HNSCC cells or media alone. In the presence of premalignant lesion cell-conditioned media, CD4(+) T cell expression of the IL-2 receptor CD25 and CD8(+) T cell expression of the activation marker CD69 was greater, compared to what was induced in HNSCC cell-conditioned media or media alone. CONCLUSION Premalignant lesion cells promote a proinflammatory environment and induce immune changes before HNSCC tumors are established.
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Affiliation(s)
- Sara D Johnson
- Research Service (151) Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, U.S.A. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A. Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, U.S.A
| | - Corinne Levingston
- Research Service (151) Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, U.S.A
| | - M Rita I Young
- Research Service (151) Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, U.S.A. Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, U.S.A. Department of Medicine, Medical University of South Carolina, Charleston, SC, U.S.A.
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Hartmann S, Bhola NE, Grandis JR. HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment. Clin Cancer Res 2016; 22:4005-13. [PMID: 27370607 DOI: 10.1158/1078-0432.ccr-16-0951] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/08/2016] [Indexed: 12/21/2022]
Abstract
Studies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread, and therapeutic failure. The EGFR is the only FDA-approved therapeutic target, yet responses to cetuximab have been limited. Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met, has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis, and angiogenesis has been investigated in HNSCC, leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review, we discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Clin Cancer Res; 22(16); 4005-13. ©2016 AACR.
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Affiliation(s)
- Stefan Hartmann
- Department of Otolaryngology, University of California San Francisco, San Francisco, California. Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Neil E Bhola
- Department of Otolaryngology, University of California San Francisco, San Francisco, California
| | - Jennifer R Grandis
- Department of Otolaryngology, University of California San Francisco, San Francisco, California.
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Echarri MJ, Lopez-Martin A, Hitt R. Targeted Therapy in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (LA-R/M HNSCC). Cancers (Basel) 2016; 8:cancers8030027. [PMID: 26927178 PMCID: PMC4810111 DOI: 10.3390/cancers8030027] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 02/16/2016] [Accepted: 02/16/2016] [Indexed: 01/07/2023] Open
Abstract
Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing.
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Affiliation(s)
- María José Echarri
- Department of Medical Oncology, Hospital Universitario Severo Ochoa, Avenida Orellana s/n, Leganés, 28911 Madrid, Spain.
| | - Ana Lopez-Martin
- Department of Medical Oncology, Hospital Universitario Severo Ochoa, Avenida Orellana s/n, Leganés, 28911 Madrid, Spain.
| | - Ricardo Hitt
- Department of Medical Oncology, Hospital Universitario Severo Ochoa, Avenida Orellana s/n, Leganés, 28911 Madrid, Spain.
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Swiecicki PL, Malloy KM, Worden FP. Advanced oropharyngeal squamous cell carcinoma: Pathogenesis, treatment, and novel therapeutic approaches. World J Clin Oncol 2016; 7:15-26. [PMID: 26862488 PMCID: PMC4734935 DOI: 10.5306/wjco.v7.i1.15] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 10/07/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Oropharyngeal cancer accounts for approximately 2.8% of newly cancer cases. Although classically a tobacco related disease, most cases today are related to infection with human papilloma virus (HPV) and present with locally advanced tumors. HPV related tumors have been recognized as a molecularly distinct entity with higher response rates to therapy, lower rates of relapse, and improved overall survival. Treatment of oropharyngeal cancer entails a multi-disciplinary approach with concomitant chemoradiation. The role of induction chemotherapy in locally advanced tumors continues to be controversial however large studies have demonstrated no difference in survival or time to treatment failure. Surgical approaches may be employed with low volume oropharyngeal cancers and with development new endoscopic tools, more tumors are able to be resected via an endoscopic approach. Given advances in the understanding of HPV related oropharyngeal cancer, ongoing research is looking at ways to minimize toxicities via de-intensification of therapy. Unfortunately, some patients develop recurrent or metastatic disease. Novel therapeutics are currently being investigated for this patient population including immunotherapeutics. This review discusses the current understanding of the pathogenesis of oropharyngeal cancer and treatment. We also discuss emerging areas of research as it pertains to de-intensification as well novel therapeutics for the management of metastatic disease.
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Innovative perspectives of immunotherapy in head and neck cancer. From relevant scientific rationale to effective clinical practice. Cancer Treat Rev 2016; 43:113-23. [PMID: 26827699 DOI: 10.1016/j.ctrv.2016.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 12/17/2015] [Accepted: 01/06/2016] [Indexed: 01/05/2023]
Abstract
It is now well established that head and neck cancer carcinogenesis is characterized by genetic instability and several immune defects, leading to unique host-tumor interactions. In such condition, recent improved comprehension and relevant findings could lead to identification of innovative molecular therapeutic targets, achieving considerable clinical and translational research. This review aims to summarize and to highlight most recent and relevant scientific rationale in this era of immunotherapy revival, and to correlate it to the near future clinical practice for the management of this challenging disease.
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Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, Ferris RL. Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Res 2015; 76:1031-43. [PMID: 26676749 DOI: 10.1158/0008-5472.can-15-2001] [Citation(s) in RCA: 250] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 11/05/2015] [Indexed: 02/07/2023]
Abstract
Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
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Affiliation(s)
| | | | - Sumita Trivedi
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yu Lei
- Department of Periodontics and Oral Medicine, School of Dentistry and Department of Otolaryngology-Head and Neck Surgery, School of Medicine. University of Michigan, Ann Arbor, Michigan
| | - Uma Chandran
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Raja R Seethala
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Gordon J Freeman
- Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Robert L Ferris
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
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Chen TC, Wu CT, Wang CP, Hsu WL, Yang TL, Lou PJ, Ko JY, Chang YL. Associations among pretreatment tumor necrosis and the expression of HIF-1α and PD-L1 in advanced oral squamous cell carcinoma and the prognostic impact thereof. Oral Oncol 2015; 51:1004-1010. [PMID: 26365985 DOI: 10.1016/j.oraloncology.2015.08.011] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The treatment strategies for advanced oral squamous cell carcinoma (OSCC), especially with necrotic changes, are not effective. The programmed death ligand 1 (PD-L1) immune escape may be one of the underlying sources of resistance. Furthermore, anti-PD-L1 directed immunotherapy may be another choice for adjuvant therapy. Therefore, the expression of PD-L1 in advanced OSCC with necrotic changes is very important. MATERIALS AND METHODS A total of 218 eligible patients with advanced stage (stage III/IV) OSCC and neck metastasis were enrolled. The presence of necrosis was reviewed by pretreatment magnetic resonance imaging. Paired paraffin-embedded primary tumor and metastatic lymph nodes (LN) sections were stained with antibodies against hypoxia-inducible factor-1α (HIF-1α) and PD-L1. Moderate-to strong HIF-1α nuclear staining in >10% and cell surface PD-L1 expression in >5% of OSCC cells were recorded as a positive result. RESULTS For advanced OSCC with necrotic changes, there was substantial agreement in primary tumor (kappa value 0.54) and almost perfect agreement in metastatic LN (kappa value 0.86) between HIF-1α and PD-L1 expression. The patients with both necrosis and positive PD-L1 expression in OSCC surrounding necrosis had worse disease control and survival outcomes. After multivariate analysis, metastatic LN necrosis and positive PD-L1 expression were found to be significant independent adverse factors. CONCLUSION Advanced OSCC patients with both necrosis and positive PD-L1 expression in OSCC surrounding necrosis had worse outcome. The aggressive behavior of advanced OSCC could be partially related to PD-L1 immune escape. These patients may be good candidates for anti-PD-L1 immunotherapy.
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Affiliation(s)
- Tseng-Cheng Chen
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Chen-Tu Wu
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Cheng-Ping Wang
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Wan-Lun Hsu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Tsung-Lin Yang
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Pei-Jen Lou
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Jenq-Yuh Ko
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Yih-Leong Chang
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan.
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Li Q, Prince MEP, Moyer JS. Immunotherapy for head and neck squamous cell carcinoma. Oral Oncol 2015; 51:299-304. [PMID: 25624094 DOI: 10.1016/j.oraloncology.2014.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 11/24/2014] [Accepted: 12/10/2014] [Indexed: 01/30/2023]
Abstract
OBJECTIVES To review the current state of immunotherapy of head and neck squamous cell carcinoma. MATERIALS AND METHODS Review of the literature with emphasis on clinical trial data. RESULTS Patients with head and neck squamous cell carcinoma (HNSCC) have long been known to be immunosuppressed. This impairment of the immune system is believed, at least in part, to underlie the poor outcomes in this patient population. Modulating the immune system to improve cancer outcomes is an attractive concept in this difficult to treat population. CONCLUSION New studies have started to unravel the mechanisms of immunosuppression and new therapies are being developed to exploit this new information.
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Affiliation(s)
- Qiao Li
- University of Michigan Comprehensive Cancer Center, 1500 E Medical Center Dr., Ann Arbor, MI 48109, United States
| | - Mark E P Prince
- University of Michigan Comprehensive Cancer Center, 1500 E Medical Center Dr., Ann Arbor, MI 48109, United States
| | - Jeffrey S Moyer
- University of Michigan Comprehensive Cancer Center, 1500 E Medical Center Dr., Ann Arbor, MI 48109, United States.
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