title: CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice.
abstract: 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.
authors.affiliation: Cancer Therapy and Research Center, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Linda F
authors.initials: LF
authors.lastname: Thompson
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D000241:Adenosine / Q000502:physiology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D005260:Female; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D011828:Radiation Chimera; D015290:Second Messenger Systems / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D047368:Tumor Burden
chemical_list: C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D000244:Adenosine Diphosphate; D015720:5'-Nucleotidase; D000241:Adenosine