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 2

Tumor-infiltrating CD8+ T cells accumulate preferentially in CD73 KO hosts.

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Tumor-infiltrating CD8+ T cells accumulate preferentially in CD73 KO hos...
(A) Representative flow cytometric analysis of tumor-infiltrating immune cells from EG7-bearing WT or CD73 KO mice collected 14 days after tumor inoculation. (B and C) Percent CD4+TCRVβ+, CD8+TCRVβ+, Gr1+CD11b+, and CD49b+NK1.1+ cells in tumor infiltrates of WT or CD73 KO mice collected 14 days after inoculation with EG7 (B) or B16-SIY (C) tumor cells (n = 5). (D) Frequency of pentamer+CD8+ cells specific for the OVA epitope SIINFEKL in infiltrates from mice in B, as determined by flow cytometry (n = 5). (E) Frequency of dimer+CD8+ cells specific for the epitope SIYRYYGL in infiltrates from mice in C, as determined by flow cytometry (n = 5). (F) Representative immunohistochemical staining using anti-CD8 mAb on EG7 tumor tissue sections obtained from A. Original magnification, ×10 (top and middle); ×40 (bottom). (G) Representative dot plots of Foxp3 expression in B16-SIY tumor-infiltrating CD4+ cells. Percent Foxp3+ cells is indicated within plots and summarized (n = 3). Data (mean ± SD) are representative of 3 independent experiments. *P < 0.05; **P < 0.01.