Role of TGF-β Signaling in Generation of CD39+CD73+ Myeloid Cells in Tumors

Abstract

There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and pro-angiogenic properties of myeloid cells. We have previously shown that the deletion of the TGFβ type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth suggesting pro-tumorigenic effect of TGFβ signaling. In this study, we tested the hypothesis that TGFβ drives differentiation of myeloid-derived suppressor cells (MDSCs) into pro-tumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from MMTV-PyMT/TGFRIIKO mice, an increased level of TGFβ protein was associated with further increase in number of CD39+CD73+ TDMMCs compared to MMTV-PyMT/TGFRIIWT control tumors with intact TGFβ signaling. Using genetic and pharmacological approaches, we demonstrated that the TGFβ signaling mediates maturation of MDSCs into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGFβ signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels and diminished progression of both Lewis Lung carcinoma and spontaneous mammary carcinomas. We propose that TGFβ signaling can directly induce the generation of CD39+CD73+ TDMMCs, thus contributing to the immunosuppressive, pro-angiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.

Anti-CD73 in Cancer Immunotherapy: Awakening New Opportunities

“…MDSCs comprise a heterogeneous population of immature myeloid cells, including myeloid progenitors and precursors of macrophages, granulocytes, and dendritic cells [59] [60]. Once activated, MDSCs produce arginase 1, inducible nitric oxide synthase, IDO, NADPH oxidase and a plethora of immunosuppressive cytokines [59].…”

“…The activation of A 2B receptors on myeloid precursors prompts the expansion of granulocytic MDSCs, thus creating a positive feedback mechanism that further facilitates the generation of adenosine and enhances immunosuppression[62]. TGF-β promotes the maturation of myeloid-derived suppressor cells into terminally differentiated myeloid mononuclear cells (TDMMC), and induces high levels of CD39/CD73 expression and increased adenosine-generating capacity[60]. The disruption of TGF-β signaling in myeloid cells decreases the accumulation of TDMMCs expressing CD39 and CD73, and is followed by increased infiltration of T lymphocytes, reduced density of blood vessels, and decreased cancer growth[60].…”

“…TGF-β promotes the maturation of myeloid-derived suppressor cells into terminally differentiated myeloid mononuclear cells (TDMMC), and induces high levels of CD39/CD73 expression and increased adenosine-generating capacity[60]. The disruption of TGF-β signaling in myeloid cells decreases the accumulation of TDMMCs expressing CD39 and CD73, and is followed by increased infiltration of T lymphocytes, reduced density of blood vessels, and decreased cancer growth[60]. …”

Expression of adenosine receptors in monocytes from patients with bronchial asthma

“…We have shown previously that adenosine, acting via A 2B receptors, was involved in the augmentation of pro-inflammatory activation of monocytes [14,26,29]. …”

Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions

“…The expression of CD39 and CD73 in tumors is mainly induced by hypoxia [32] and by the presence of immunosuppressive factors such as TGF-β [33]. This expression is generally associated with poor prognosis [32, 34].…”