CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice
Long Wang, … , Tyler J. Curiel, Bin Zhang
Long Wang, … , Tyler J. Curiel, Bin Zhang
Published May 2, 2011
Citation Information: J Clin Invest. 2011;121(6):2371-2382. https://doi.org/10.1172/JCI45559.
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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

Long Wang, Jie Fan, Linda F. Thompson, Yi Zhang, Tahiro Shin, Tyler J. Curiel, Bin Zhang

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Figure 8

Pharmacological blockade of CD73 activity inhibits tumor growth and augments the efficacy of adoptive T cell therapy.

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Pharmacological blockade of CD73 activity inhibits tumor growth and augm...
(A and B) WT (A) or CD73 KO (B) mice (n = 5 per group) were challenged s.c. with 106 B16-SIY cells. 1 week later, mice were treated with APCP (20 mg/kg i.v.) once daily for 1 week, then twice weekly, and tumor volume was measured. (C and D) WT mice (n = 5 per group) were s.c. challenged with 106 B16-SIY cells. 10 days later, mice were treated with either APCP as described above (C) or 100 μg TY/23 (D) 2 times weekly and adoptively transferred with 5 × 106 2C T cells 13 days after tumor challenge as indicated. Tumor volumes were measured at the indicated times. (E) Female WT mice were inoculated i.p. with 107 ID8 cells. 1 week later, tumor-bearing mice were left untreated or transferred with 107 ID8-reactive T cells i.p. and/or treated with TY/23 as described above. Survival of the mice (n = 5–8 per group) was measured. Data are representative of 2 independent experiments. *P < 0.05; **P < 0.01.