Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma

Authors: Si-Rui Ma, Wei-Wei Deng, Jian-Feng Liu, Liang Mao, Guang-Tao Yu, Lin-Lin Bu, Ashok B. Kulkarni, Wen-Feng Zhang, Zhi-Jun Sun

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC.

Methods

The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues. The immunotherapeutic value of A2AR blockade was assessed in vivo in genetically defined immunocompetent HNSCC mouse model.

Results

Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status. Elevated A2AR expression was also detected in recurrent HNSCC and HNSCC tissues with induction chemotherapy. The expression of A2AR was found to be significantly correlated with HIF-1α, CD73, CD8 and Foxp3. Furthermore, the increased population of CD4+Foxp3+ regulatory T cells (Tregs), which partially expressed A2AR, was observed in an immunocompetent mouse model that spontaneously develops HNSCC. Pharmacological blockade of A2AR by SCH58261 delayed the tumor growth in the HNSCC mouse model. Meanwhile, A2AR blockade significantly reduced the population of CD4+ Foxp3+ Tregs and enhanced the anti-tumor response of CD8+ T cells.

Conclusions

These results offer a preclinical proof for the administration of A2AR inhibitor on prophylactic experimental therapy of HNSCC and suggest that A2AR blockade can be a potential novel strategy for HNSCC immunotherapy.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed
2.
3.
Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2008;83:489–501.CrossRefPubMed
4.
Quan J, Johnson NW, Zhou G, Parsons PG, Boyle GM, Gao J. Potential molecular targets for inhibiting bone invasion by oral squamous cell carcinoma: a review of mechanisms. Cancer Metastasis Rev. 2012;31:209–19.CrossRefPubMed
5.
Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL. Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004;10:3755–62.CrossRefPubMed
6.
7.
Punt S, Dronkers EA, Welters MJ, Goedemans R, Koljenovic S, Bloemena E, et al. A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17(+) cell frequency. Cancer Immunol Immunother. 2016;65:393–403.CrossRefPubMedPubMedCentral
8.
Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol. 2006;177:6780–6.CrossRefPubMed
9.
Bergmann C, Strauss L, Wang Y, Szczepanski MJ, Lang S, Johnson JT, et al. T regulatory type 1 cells in squamous cell carcinoma of the head and neck: mechanisms of suppression and expansion in advanced disease. Clin Cancer Res. 2008;14:3706–15.CrossRefPubMedPubMedCentral
10.
Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24:5373–80.CrossRefPubMed
11.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.CrossRefPubMed
12.
Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: how do they suppress immune responses? Int Immunol. 2009;21:1105–11.CrossRefPubMed
13.
Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998;188:287–96.CrossRefPubMedPubMedCentral
14.
Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. Oncoimmunology. 2013;2:e25961.CrossRefPubMedPubMedCentral
15.
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A. 2006;103:13132–7.CrossRefPubMedPubMedCentral
16.
Raskovalova T, Huang X, Sitkovsky M, Zacharia LC, Jackson EK, Gorelik E. Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J Immunol. 2005;175:4383–91.CrossRefPubMed
17.
Hatfield SM, Sitkovsky M. Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators. Oncoimmunology. 2015;4:e1052934.CrossRefPubMedPubMedCentral
18.
Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci U S A. 2013;110:14711–6.CrossRefPubMedPubMedCentral
19.
Waickman AT, Alme A, Senaldi L, Zarek PE, Horton M, Powell JD. Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol Immunother. 2012;61:917–26.CrossRefPubMed
20.
Young A, Mittal D, Stagg J, Smyth MJ. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 2014;4:879–88.CrossRefPubMed
21.
Kunzli BM, Bernlochner MI, Rath S, Kaser S, Csizmadia E, Enjyoji K, et al. Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal. 2011;7:231–41.CrossRefPubMedPubMedCentral
22.
Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MW, Darcy PK, et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res. 2011;71:2892–900.CrossRefPubMed
23.
Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010;107:1547–52.CrossRefPubMedPubMedCentral
24.
Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B, Abbott R, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med. 2015;7:277ra30.CrossRefPubMedPubMedCentral
25.
Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M. The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol. 2012;3:190.CrossRefPubMedPubMedCentral
26.
Yu GT, Bu LL, Huang CF, Zhang WF, Chen WJ, Gutkind JS, et al. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget. 2015;6:42067–80.PubMedPubMedCentral
27.
Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, et al. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol. 2013;31:744–51.CrossRefPubMed
28.
Sun ZJ, Zhang L, Hall B, Bian Y, Gutkind JS, Kulkarni AB. Chemopreventive and chemotherapeutic actions of mTOR inhibitor in genetically defined head and neck squamous cell carcinoma mouse model. Clin Cancer Res. 2012;18:5304–13.CrossRefPubMedPubMedCentral
29.
Bu LL, Yu GT, Deng WW, Mao L, Liu JF, Ma SR, et al. Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5:e1130206.CrossRefPubMedPubMedCentral
30.
Estilo CL, Oc P, Talbot S, Socci ND, Carlson DL, Ghossein R, et al. Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis. BMC Cancer. 2009;9:11.CrossRefPubMedPubMedCentral
31.
Partlova S, Boucek J, Kloudova K, Lukesova E, Zabrodsky M, Grega M, et al. Distinct patterns of intratumoral immune cell infiltrates in patients with HPV-associated compared to non-virally induced head and neck squamous cell carcinoma. Oncoimmunology. 2015;4:e965570.CrossRefPubMedPubMedCentral
32.
Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer. 1994;73:187–90.CrossRefPubMed
33.
34.
Takayama H, Trenn G, Sitkovsky MV. Locus of inhibitory action of cAMP-dependent protein kinase in the antigen receptor-triggered cytotoxic T lymphocyte activation pathway. J Biol Chem. 1988;263:2330–6.PubMed
35.
Bian Y, Hall B, Sun ZJ, Molinolo A, Chen W, Gutkind JS, et al. Loss of TGF-beta signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene. 2012;31:3322–32.CrossRefPubMed
36.
37.
Bian Y, Terse A, Du J, Hall B, Molinolo A, Zhang P, et al. Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res. 2009;69:5918–26.CrossRefPubMedPubMedCentral
38.
Yu GT, Bu LL, Zhao YY, Mao L, Deng WW, Wu TF, et al. CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5:e1151594.CrossRefPubMedPubMedCentral
39.
Freiser ME, Serafini P, Weed DT. The immune system and head and neck squamous cell carcinoma: from carcinogenesis to new therapeutic opportunities. Immunol Res. 2013;57:52–69.CrossRefPubMed
40.
Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene. 2010;29:5346–58.CrossRefPubMed
41.
42.
Bonnefoy N, Bastid J, Alberici G, Bensussan A, Eliaou JF. CD39: A complementary target to immune checkpoints to counteract tumor-mediated immunosuppression. Oncoimmunology. 2015;4:e1003015.CrossRefPubMedPubMedCentral
43.
Morote-Garcia JC, Rosenberger P, Kuhlicke J, Eltzschig HK. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood. 2008;111:5571–80.CrossRefPubMed
44.
Eckert AW, Wickenhauser C, Salins PC, Kappler M, Bukur J, Seliger B. Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma. J Transl Med. 2016;14:85.CrossRefPubMedPubMedCentral
45.
Perez-Sayans M, Suarez-Penaranda JM, Pilar GD, Barros-Angueira F, Gandara-Rey JM, Garcia-Garcia A. Hypoxia-inducible factors in OSCC. Cancer Lett. 2011;313:1–8.CrossRefPubMed
46.
Liu SY, Chang LC, Pan LF, Hung YJ, Lee CH, Shieh YS. Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol. 2008;44:277–85.CrossRefPubMed
47.
Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood. 2008;111:251–9.CrossRefPubMedPubMedCentral
48.
Sitkovsky MV. T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol. 2009;30:102–8.CrossRefPubMed
49.
Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS. Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol. 2009;45:324–34.CrossRefPubMed
50.
Toda A, Piccirillo CA. Development and function of naturally occurring CD4+CD25+ regulatory T cells. J Leukoc Biol. 2006;80:458–70.CrossRefPubMed
51.
Cekic C, Day YJ, Sag D, Linden J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res. 2014;74:7250–9.CrossRefPubMedPubMedCentral
52.
Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28:690–714.CrossRefPubMed
53.
Lake RA, Robinson BW. Immunotherapy and chemotherapy--a practical partnership. Nat Rev Cancer. 2005;5:397–405.CrossRefPubMed
54.
Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 2014;21:79–91.CrossRefPubMed
55.
Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res. 2014;2:598–605.CrossRefPubMedPubMedCentral
56.
Mittal D, Young A, Stannard K, Yong M, Teng MW, Allard B, et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 2014;74:3652–8.CrossRefPubMed
57.
Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013;19:5626–35.CrossRefPubMed
Metadata
Title
Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma
Authors
Si-Rui Ma
Wei-Wei Deng
Jian-Feng Liu
Liang Mao
Guang-Tao Yu
Lin-Lin Bu
Ashok B. Kulkarni
Wen-Feng Zhang
Zhi-Jun Sun
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0665-0

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome

Letter to the Editor

Dual role for p16 in the metastasis process of HPV positive head and neck cancers

Research

Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway

Review

Circles reshaping the RNA world: from waste to treasure

Research

Discovery and validation of immune-associated long non-coding RNA biomarkers associated with clinically molecular subtype and prognosis in diffuse large B cell lymphoma

Review

Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits