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.

Role of CD73 and extracellular adenosine in disease

“…However, this outstanding paper contains elegant experimentation and provides important insights into the biology of CD73 in cancer. Crucially, this work [28] is also further validated and confirmed by Stagg et al [36]. It appears from both studies that CD73 may be targeted on tumor cells, Tregs and potentially nonhematopoietic cells in the promotion of immune responsiveness.…”

“…Here, Wang et al have shown that purinergic mechanisms are intimately involved in the regulation of tumor growth [28]. The authors show a survival benefit for Cd73 null mice bearing transplanted tumors, when compared to wild type mice.…”

“…Here, the authors clearly show that CD73 expression inhibits anti-tumor immune responses. Homing was also shown to be dependent on A2B receptor pathways, albeit whether or not through cAMP-dependent pathways remains uncertain at this time [28]. The witnessed effects could be related to adenosinergic/purinergic modulation of leukocyte homing or possibly even to induction of apoptosis.…”

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

“…Finally, our findings would be strengthened by genetic knockdown of CD73 expression. Although the authors have explored use of a CD73‐deficient MSC line, current evidence suggests that CD73 may be critical for cell proliferation 69, 70. Knockdown of this enzyme may limit MSC growth kinetics in vitro, which presents unique challenges for expansion before implantation, and thus requires further study.…”

Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases

“…4 On the host, CD73 promotes immune-evasion, and CD73 gene targeted mice have significantly retarded tumor growth and metastasis. 5,6,7 These antitumor effects were largely dependent upon the activation of CD8 C T cells, NK cells and production of IFNg. 5,6,8 Altogether, these observations indicated that the inhibition of the CD73 pathway deterred adenosine accumulation, and thus reversed immune suppression.…”