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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Research Article Oncology

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 6

Blockade of CD73 in vivo augments T cell homing to tumors.

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Blockade of CD73 in vivo augments T cell homing to tumors. Activated OT-...
Activated OT-I CD90.1 cells were labeled with CFSE and adoptively transferred into EG7-tumor bearing WT or CD73 KO mice. (A) Representative flow cytometric analyses of OT-I cells in the spleen, DLN, and EG7 tumor 24 hours after transfer. (B) Frequency and absolute number of CFSE+CD8+ OT-I cells among different tissues from EG7-bearing mice 24 hours after T cell transfer (n = 5). (C) Frequency and absolute number of CFSE+CD8+ 2C cells among different tissues from B16-SIY–bearing mice 24 hours after T cell transfer (n = 5). (D) Frequency and absolute number of CFSE+CD8+ OT-I cells among tumor tissues from EG7-bearing WT mice treated as indicated and assessed 24 hours after T cell transfer (n = 5). (E) Frequency and absolute number of CFSE+CD8+ 2C cells among tumor tissues from B16-SIY–bearing WT mice treated as indicated and assessed 24 hours after T cell transfer (n = 5). Data (mean ± SD) are representative of 3 independent experiments. *P < 0.05; **P < 0.01.