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 1

Tumor growth is inhibited in CD73 KO mice.

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Tumor growth is inhibited in CD73 KO mice. (A) Increased survival of CD7...
(A) Increased survival of CD73 KO mice challenged with ID8 ovarian tumors is T cell dependent. Female C57BL/6 WT, CD73 KO, or CD73 KO mice depleted of CD8+ T cells by anti-CD8 mAb 53.6.7 were inoculated i.p. with 1 × 107 ID8 cells (n = 6). (B and C) Suppression of tumor growth in CD73 KO mice. Mice (n = 3 or 5 per group) were inoculated with 106 EG7 (B) or B16-SIY (C) cells. White symbols, CD73 KO; black symbols, WT; each symbol represents 1 tumor-bearing mouse. (D and E) In CD73 KO mice (n = 5 per group), depletion of CD4+ T cells, CD8+ T cells, or NK cells was achieved by twice-weekly i.p. injection of control Ig or anti-CD4, anti-CD8, or anti–asialo GM1 depleting Abs, respectively, beginning 1 day prior to EG7 (D) or B16-SIY (E) challenge. (F) Survival of WT or CD73 KO mice (n = 5–8 per group) after i.p. inoculation with 107 ID8-OVA-SiCD73 (CD73-silenced) or ID8-OVA-SiNS (CD73-nonsilenced control) tumor cells. (G and H) Tumor growth was enhanced by both BM-derived and non–BM-derived host cells expressing CD73. Chimeric mice (n = 5 per group), generated by BM reconstitution, were injected s.c. with 106 EG7 (G) or B16-SIY (H) cells. Data (mean ± SD) are representative of 3 independent experiments (A and F), at least 10 independent experiments (B and C), or 2 (G and H) independent experiments. *P < 0.05 vs. all other groups or as denoted by brackets.