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 7

CD73 expression by CD4+CD25+ Tregs inhibits antitumor T cell immunity and facilitates tumor growth.

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CD73 expression by CD4+CD25+ Tregs inhibits antitumor T cell immunity an...
(A and B) Purified OT-I CD8+CD90.1+ T cells (2 × 106) were injected i.v. into WT mice (n = 3 per group) with or without 106 splenic CD4+CD25+ Tregs derived from EG7-bearing WT or CD73 KO mice. The next day, 106 EG7 cells were injected s.c. into the T cell recipients. 3 days later, percent transferred T cells in spleen and DLN (A) and percent IFN-γ+ cells among the transferred cells in spleen (B) were determined by flow cytometry (n = 3). (C) For CD25+ T cell depletion, splenic T cells were further purified by negative selection using magnetic bead–conjugated anti-CD25 Ab. Rag1–/– mice (n = 5 per group) were challenged with 106 B16-SIY cells 24 hours after receiving 107 total T cells or CD25-depleted T cells from naive WT or CD73 KO mice. (D) Treg depletion using DT inhibited tumor growth. WT or CD73 KO mice (n = 5 per group) were challenged with 106 B16-SIY cells. 3 days later, mice were treated with DT (2 μg/mouse twice weekly). (E) Adoptive transfer of WT Tregs, but not CD73 KO Tregs, reversed the tumor-inhibiting advantage of host CD73 deficiency. CD4+CD25+ Tregs derived from WT or CD73 KO mice were injected i.v. into CD73 KO mice. The next day, 106 B16-SIY cells were challenged. Data (mean ± SD) are representative of 3 (A and B) or 2 (C–E) independent experiments. *P < 0.05; **P < 0.01.