CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment

Abstract

We sought to investigate how peripheral blood and tumorinfiltrating NK cells differ in patients with breast cancer and sarcoma, and if tumor-infiltrating NK cells develop immunoregulatory functions. Compared with peripheral blood NK cells, tumorinfiltrating NK cells undergo phenotypic changes and acquire the expression of several immune checkpoint receptors. The expression of these immune checkpoint molecules was significantly higher on NK cells expressing CD73. Mechanistically, NK cells and IL-10 (21, 22). More recently in the context of cancer, CD56 + CD3cells in patients with ovarian cancer suppressed the growth of T cells, as observed within an ex vivo expansion of tumor-infiltrating lymphocytes (TILs). Even though it was demonstrated that the suppression was mediated by NKp46 engagement, the underlying mechanisms of how NK cells suppress are still unclear (23). It is also still unclear how conventional NK cells can undergo a phenotypic switch to suppress other TIL populations and contribute to tumor immune escape.

PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates

“…These results are in agreement with a recent report where tumor infiltrating NK cells upregulate CD73 + and undergo transcriptional reprogramming which leads to an increased IL-10 and TGF-β production. 53 Understanding the relationship between NK cell activation status, these immunosuppressive cytokines, and the expansion of MoMDSCs could be a key component in antitumoral immunity.…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Hypoxiainducible factors (HIFs) are strongly linked to increasing CD73 (109), A2AR (110), and A2BR (111) gene expression and collaborates to increase extracellular adenosine/adenosine receptor signaling for dampening inflammation (46,47). Interestingly, recent studies show tumor cells can reprogram NK cells to gain immunosuppressive functions [e.g., increase IL-10 and transforming growth factor-β (TGF-β) production via signal transducer and activator of transcription 3 (STAT3) transcriptional activity, suppressing IFN-γ production] (112). The effects are not mediated through adenosine receptors, suggesting other mechanisms are involved and may not involve the production of extracellular adenosine (112).…”

“…Interestingly, recent studies show tumor cells can reprogram NK cells to gain immunosuppressive functions [e.g., increase IL-10 and transforming growth factor-β (TGF-β) production via signal transducer and activator of transcription 3 (STAT3) transcriptional activity, suppressing IFN-γ production] (112). The effects are not mediated through adenosine receptors, suggesting other mechanisms are involved and may not involve the production of extracellular adenosine (112).…”

CD73 Overexpression Promotes Progression and Recurrence of Papillary Thyroid Carcinoma

“…In the tumor microenvironment, fibroblasts, endothelial cells, and Tregs can express CD73 and enhance antitumor immunity [ 26 ]. NK cells expressing CD73 can undergo phenotypic changes that acquire the expression of immune checkpoint receptors and contribute to tumor immune escape [ 27 ]. Therefore, our study does not exclude the possibility that CD73 expression by the PTC microenvironment may play role in antitumor immunity, although inflammatory cells and stromal cells were negative for CD73 by immunohistochemistry.…”