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 3

Host CD73 impairs endogenous antitumor T cell immunity.

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Host CD73 impairs endogenous antitumor T cell immunity. (A) Representati...
(A) Representative flow cytometric analyses of antitumor T cells in spleen from EG7-bearing WT or CD73 KO mice 14 days after tumor inoculation. (B) The H-2Kb-OVA/SIINFEKL pentamer was used to track OVA-specific CD8+ T cells. Pentamer+CD8+ and CD8+IFN-γ+ T cell frequency in response to SIINFEKL peptide is summarized (n = 5). (C) The H-2Kb-SIYRYYGL-IgG dimer was used to track SIY-specific CD8+ T cells in spleen from B16SIY-tumor bearing WT or CD73 KO mice 14 days after tumor inoculation. Dimer+CD8+ and CD8+IFN-γ+ cell frequency in response to SIYRYYGL peptide is summarized (n = 5). (D) Representative flow cytometric analyses of in vivo antigen-specific killing capacity of antitumor T cells from EL4- or EG7-bearing WT and CD73 KO mice. Equal numbers (107 cells each) of CFSEhi SIINFEKL peptide-pulsed and CFSElo non–peptide-pulsed WT splenocytes were adoptively transferred into tumor-bearing mice. Numbers denote percentage of SIINFEKL peptide-pulsed target cell killing in spleen, calculated as described in Methods. (E) Percent killing for EG7-bearing mice (n = 5). (F) Percent killing of adoptively transferred SIYRYYGL peptide-pulsed splenocytes from parallel experiments involving B16-SIY–bearing mice (n = 5). Data (mean ± SD) are representative of 3 independent experiments. *P < 0.05.