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

Abstract

BackgroundCancer 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.MethodsThe 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.ResultsImmunostaining 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0665-0) contains supplementary material, which is available to authorized users.

A defect in KCa3.1 channel activity limits the ability of CD8 + T cells from cancer patients to infiltrate an adenosine-rich microenvironment

“…We showed that adenosine inhibited CD8 + T cell chemotaxis, and this effect was enhanced in cells from HNSCC patients. This is consistent with immunohistochemical data of various solid tumors showing an inverse correlation between CD73 in the tumor and the infiltration of CD8 + TILs (46–50). The advantage of the studies we have performed here over the correlative studies in tissue samples is that we have used a collagen-rich 3D microenvironment where we have full control over the experimental conditions used, while in vivo, the TME is a complex mixture of metabolic and waste products and tumor cells.…”

Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

“…Adenosine, a purine metabolite present at high concentration in the TME, also acts by limiting the activity of protective immune infiltrates, including NK cells, and enhancing that of Tregs and MDSCs (128). Adenosine accumulated in the TME by CD39 and CD73, causing inhibition of tumor-infiltrating NK cells by binding to the purinergic adenosine A 2A receptor expressed on cell surface (129)(130)(131)(132)(133). Reduction of adenosine by blocking both CD73 and the A 2A receptor was shown to affect tumor growth and promote recruitment of tumor-infiltrating NK cells (134).…”

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…The inhibition role of ADO in antitumor T cells is mediated by A2AR and A2BR. Pharmacological blockade of A2AR not only enhances CD8 + T cells anti-tumor response but also reduces the population of Tregs [62]. A2AR antagonist or silence by siRNA could improve the inhibition of tumor growth, destruction of metastases and prevention of neovascularization by anti-tumor T cells [63].…”