Dataset Information

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

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.

SUBMITTER: Ma SR

PROVIDER: S-EPMC5461710 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Ma Si-Rui SR Deng Wei-Wei WW Liu Jian-Feng JF Mao Liang L Yu Guang-Tao GT Bu Lin-Lin LL Kulkarni Ashok B AB Zhang Wen-Feng WF Sun Zhi-Jun ZJ

Molecular cancer 20170607 1

<h4>Background</h4>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.<h4>Methods</h4>The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, ...[more]

PMID: 28592285

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Project description:BackgroundImmune cell heterogenicity is known to determine the therapeutic response to cancer progression. Neoadjuvant chemoimmunotherapy (NACI) has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism behind this clinical response is unknown. The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting NACI response in advanced HNSCC.MethodsWe performed combined single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence (mIHC) staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell (TIL) subtype, CD103+ CD8+ TILs, associated with clinical response, while both in vitro and in vivo assays were carried out to determine its antitumor efficiency. The regulatory mechanism of the CD103+ CD8+ TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.ResultsWe established intratumoral CD103+ CD8+ TILs density as a determinant of NACI efficacy in cancers. Our scRNA-seq results indicated that the population of CD103+ CD8+ TILs was dramatically increased in the responders of NACI-treated HNSCC patients, while mIHC analysis confirmed the correlation between intratumoral CD103+ CD8+ TILs density and NACI efficacy in HNSCC patients. Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI. Functional assays showed that CD103+ CD8+ TILs were tumor-reactive T cells, while programmed cell death protein-1 (PD-1) blockade enhanced CD103+ CD8+ TILs cytotoxicity against tumor growth in vivo. Mechanistically, targeting the triggering receptor expressed on myeloid cells 2-positive (TREM2+ ) macrophages might enhance the population of CD103+ CD8+ TILs and facilitate antitumor immunity during NACI treatment.ConclusionsOur study highlights the impact of intratumoral CD103+ CD8+ TILs density on NACI efficacy in different cancers, while the efforts to elevate its population warrant further clinical investigation.

Project description:BackgroundThe occurrence of head and neck squamous cell carcinoma (HNSCC) is closely related to the immune system. The integration of traditional treatment methods and immunotherapy will be the future development direction of cancer treatment. But immunotherapy also has its limitations: a lot of basic research is going on, but the translation from basic to clinical is still not enough, and there are still few drugs approved for use.This study aimed to explore the clinical significance of the tumor immune microenvironment in HNSCC.MethodsSix clinically obtained postoperative cases were analyzed using multiplex immunohistochemistry (mIHC) to observe the tumor immune microenvironment and analyze infiltrating immune cells. Correlations between infiltrating immune cells from The Cancer Genome Atlas (TCGA) database and clinicopathological features of 510 HNSCC patients were then analyzed. Kaplan-Meier survival analysis was used to detect the relationship between the expression of different immune cells and the prognosis of HNSCC patients, and univariate and multivariate Cox regression analyses were used to analyze the prognostic factors associated with HNSCC patients. We validated the prognostic and predictive accuracy based on the expression of CD8+ T-cells in an independent group of 510 patients.ResultsWe detected infiltration of CD8+ T cells, NK cells, and macrophages in patients with laryngeal squamous cell carcinoma by multiplex immunofluorescence. The infiltration of the three types of immune cells in the tumor stroma was significantly higher than in the tumor parenchyma. Our results also showed the infiltration of CD8+ T cells was associated with prognosis, and the COX regression model showed CD8+ T cells were an independent prognostic factor in HNSCC patients. The higher density of infiltrating CD8+ T cells had the better prognosis. In addition, we developed a nomogram for clinical use that integrated the CD8+ T-cells-based classifier and three clinicopathological risk factors to predict the prognosis of HNSCC patients.ConclusionsCD8+ T-cell exhaustion in the tumor microenvironment of HNSCC determines poor prognosis and can be combined with the tumor stage to improve the accuracy of prognosis assessment in HNSCC patients.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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