Specific blockade CD73 alters the “exhausted” phenotype of T cells in head and neck squamous cell carcinoma

• Published in: International journal of cancer 2018-09, Vol.143 (6), p.1494-1504
• Main Authors: Deng, Wei‐Wei, Li, Yi‐Cun, Ma, Si‐Rui, Mao, Liang, Yu, Guang‐Tao, Bu, Lin‐Lin, Kulkarni, Ashok B., Zhang, Wen‐Feng, Sun, Zhi‐Jun
• Format: Article
• Language: English
• Subjects: 5'-Nucleotidase - antagonists & inhibitors; 5'-Nucleotidase - genetics; 5'-Nucleotidase - metabolism; Adenosine; AMP; Animals; Antibodies, Monoclonal - pharmacology; Apoptosis; Biomarkers, Tumor; Cancer; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD73; CD73 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell death; Cell Proliferation; CTLA-4 Antigen - metabolism; cytotoxic T‐lymphocyte‐associated protein 4; Follow-Up Studies; Genotype & phenotype; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Head & neck cancer; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; Humans; Immune response; Immune Tolerance - immunology; Immunoregulation; Immunosuppression; Immunosurveillance; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Medical research; Mice; Mice, Knockout; Mice, Transgenic; Monoclonal antibodies; Nucleotidase; Patients; Phenotype; Phenotypes; Prognosis; programmed cell death protein 1; PTEN Phosphohydrolase - physiology; Receptor, Transforming Growth Factor-beta Type I - physiology; Squamous cell carcinoma; Survival Rate; T cell; Tumor cells; Tumor Cells, Cultured
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.31534

The adenosine‐induced immunosuppression hampers the immune response toward tumor cells and facilitates the tumor cells to evade immunosurveillance. CD73, an ecto‐5‐nucleotidase, is the ectoenzyme dephosphorylating extracellular AMP to adenosine. Here, using immunocompetent transgenic head and neck squamous cell carcinoma (HNSCC) mouse model, immune profiling showed high expression of CD73 on CD4+ and CD8+ T cells was associated with an “exhausted” phenotype. Further, treatment with anti‐CD73 monoclonal antibody (mAb) significantly blunted the tumor growth in the mouse model, and the blockade of CD73 reversed the “exhausted” phenotype of CD4+ and CD8+ T cells through downregulation of total expression of PD‐1 and CTLA‐4 on T cells. Whereas the population of CD4+CD73hi/CD8+CD73hi T cells expressed higher CTLA‐4 and PD‐1 as compared to untreated controls. In addition, the human tissue microarrays showed the expression of CD73 is upregulated on tumor infiltrating immune cells in patients with primary HNSCC. Moreover, CD73 expression is an independent prognostic factor for poor outcome in our cohort of HNSCC patients. Altogether, these findings highlight the immunoregulatory role of CD73 in the development of HNSCC and we propose that CD73 may prove to be a promising immunotherapeutic target for the treatment of HNSCC. What's new? Tumor cells employ various immunosuppressive mediators to evade immune detection and thereby escape mechanisms for tumor elimination. While cancer immunotherapeutic agents have been developed to counter this, some patients fail to respond, necessitating the development of alternative immunosuppressive approaches. Here, immune profiling in a head and neck squamous cell carcinoma (HNSCC) mouse model revealed high expression of the ecto‐5‐nucleotidase CD73 on CD4+ and CD8+ T cells. Treatment with an anti‐CD73 antibody suppressed tumor growth and restored T‐cell effector function. CD73 expression was further found to be upregulated in human HNSCC tissues, where it was prognostic for poor outcome.