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

Abstract

The emerging role for CD73 in driving cancer growth and metastasis has presented opportunities to develop anti-CD73 monoclonal antibodies (mAbs) in the treatment of human cancers. Blockade of CD73 by antagonistic CD73 mAbs ameliorates tumor growth and metastasis via the inhibition of enzymatic and non-enzymatic CD73 pathways. In this study, we investigated whether Fc-receptor cross-linking represented a non-redundant mechanism by which anti-CD73 mAbs exert potent suppression of solid tumors and metastases. We engineered four anti-CD73 mAbs, each different in their ability to modulate CD73 enzymatic function and bind Fc receptors. mAbs recognizing a similar epitope of CD73 (CD73-04, TY/23 and 2C5) displayed the greatest antitumor activity. Importantly, we observed that the optimal control of metastasis by anti-CD73 mAbs involved primarily Fc receptor engagement, while suppression of solid tumors required both, enzyme inhibition and activation of Fc receptors. Engagement of Fc-receptors was also essential for optimal anti-metastatic effect in combination with either A2AR inhibitor or anti-PD-1 mAb treatment. The control of experimental metastases relied on the activation of host NK cells and IFNg, while NK cells, CD8 C T cells and IFNg were needed for effective antitumor effect in the spontaneous metastases model. These observations advance our understanding of the enzymatic and non-enzymatic functions of anti-CD73 mAbs in solid tumors and metastases. Altogether, these findings will greatly assist in the design of anti-CD73 mAbs to be used as either single agents or in combination with other immunotherapeutic molecules or targeted therapies.

Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway

“…However, despite all that we have discussed so far, not all effects observed following Abcc6 silencing were mimicked by treatment with probenecid. Unlike what was previously observed in Abcc6 knockdown HepG2 cells [14], probenecid did not block cell cycle and cellular senescence, probably because it has a lesser impact on cellular metabolism, compared to what happens in response to gene silencing.…”

“…The ecto-5 -nucleotidase CD73 is able to catalyze the conversion of extracellular AMP to adenosine and phosphate; it is the main source of extracellular adenosine in all tissues in which ATP is poorly present in extracellular fluids [10,11]. CD73 is considered a key regulator in some cancer processes such as drug resistance, tumor metastasis, and tumor angiogenesis [12,13], therefore is an excellent candidate for cancer therapy [14][15][16]. In previous studies, we have reported that knockdown of Abcc6 in hepatocarcinoma cancer cells (HepG2), or the inhibition of its activity lead to the downregulation of NT5E gene, which codifies for the CD73 protein [17][18][19].…”

CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment

“…Similarly, studies reported that NK cells acquire the expression of CD73 after physical contact with human umbilical cord-derived MSCs or dental pulp stem cells (37,38). In cancer, NK cells from gastrointestinal stromal tumors (GISTs) have been found to express higher levels of surface CD73 (39). Yet, the current understanding of tumor-infiltrating NK cells is unclear with regard to their robustness in phenotype and function.…”

FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy

“…Three CD73 blocking antibodies have been entered into clinical trials (i.e., BMS-986179, CPI-006, and MEDI9447). Compared with small-molecule inhibitors, anti-CD73 mAbs offer the possibility of directly targeting both enzymatic and non-enzymatic CD73 pathways (148). In vitro data showed that MEDI9447 (human IgG1 variant) could inhibit the enzymatic activity of both soluble- and membrane-bound CD73 through prevention of the conformational transition of CD73 to an active state, and could induce internalization of membrane-bound CD73, and restore T-cell proliferation from the inhibition by AMP (149, 150).…”