CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice

• Published in: The Journal of clinical investigation Vol. 121; no. 6; pp. 2371 - 2382
• Main Authors: Wang, Long, Fan, Jie, Thompson, Linda F, Zhang, Yi, Shin, Tahiro, Curiel, Tyler J, Zhang, Bin
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-06-2011
• Subjects: 5'-Nucleotidase - antagonists & inhibitors; 5'-Nucleotidase - deficiency; 5'-Nucleotidase - immunology; 5'-Nucleotidase - physiology; Adenosine; Adenosine - physiology; Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - pharmacology; Adenosine Diphosphate - therapeutic use; Animals; Antigens; Biomedical research; Chemotaxis, Leukocyte; Disease Progression; Enzymes; Female; Growth; Immunotherapy; Immunotherapy, Adoptive; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Lymphoma, Non-Hodgkin - immunology; Lymphoma, Non-Hodgkin - pathology; Lymphoma, Non-Hodgkin - therapy; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular Targeted Therapy; Ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Peritoneal Neoplasms - immunology; Peritoneal Neoplasms - secondary; Peritoneal Neoplasms - therapy; Radiation Chimera; Second Messenger Systems - physiology; T cells; T-Lymphocytes - immunology; T-Lymphocytes, Regulatory - immunology; Tumor Burden; Tumors; United States; Illinois
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci45559

CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell-dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4⁺CD25⁺ Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy.