Myeloid Expression of Adenosine A2A Receptor Suppresses T and NK Cell Responses in the Solid Tumor Microenvironment

Abstract

High concentrations of adenosine in tumor microenvironments inhibit anti-tumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2ARs) that suppress their activation and inhibit immune killing of tumors, a role for myeloid-cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2af/f–LysMCre+/− mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL-12 expression in tumor-associated macrophages and with > 90% reductions in IL-10 expression in tumor-associated macrophages, dendritic cells and Ly6C+ or Ly6G+ myeloid-derived suppressor cells. Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and NK cells. Depletion of CD8+ T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8+ T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen specific CD8+ T cells in lung infiltrates. Overall the findings indicate that myeloid cell A2ARs have direct myelosupressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors.

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…Extracellular nucleotides also regulate the fate of immune cells, 14,35 and immunosuppressive properties of adenosine in solid carcinomas have been extensively described. 20 Moreover, hypoxia modulates immune cell sensitivity to adenosine via increase of HIF1a expression which leads to modulation of CD73 and ADORA2A.…”

“…[29][30][31] Ohta, Sitkovsky and others showed that, among the different adenosine receptors (A1, A2A, A2B and A3), 26 the adenosine receptor 2A has a major role in the attenuation of inflammation and tissue damage. 20,21,[32][33][34][35] These studies evidenced the CD39-CD73-adenosine receptor axis blockade as a promising therapeutic target. 31,[36][37][38][39][40][41][42] In line with these studies and with the objective to better understand the mechanism involved in the acquisition by TAM of an immunoregulatory phenotype, this study aimed at evaluating the impact of ATP and ATP metabolites on TAM functions.…”

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

“…[10][11][12] In contrast to these suppressive cytokines, several cytokines such as IL-2, IL-12, IL-15, IL-18, and IL-21 are known to activate NK cells both in vitro and in vivo, and are proposed to increase the therapeutic potential of these cells for adoptive therapy. 13 Due to their natural cytotoxic property in the peripheral blood, 14 the use of NK cells has been identified as one of the promising adoptive cellular immunotherapies to control cancer.…”

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

“…6,7 In contrast, peripheral regulatory T cells (pTreg) or myeloid-derived suppressor cells (MDSC) are activated by ADO signaling via A 2A R and their immunosuppressive functions are enhanced. 8,9 The role of A 1 R or A 3 R in ADO-mediated immune regulation is not entirely clear, although 5 0 -AMP was reported to be an A 1 R agonist with affinity equal to or better than that of ADO. 10 In cancer, ADO is viewed as a pro-tumor factor which suppresses antitumor functions of Teff and promotes functions of suppressor cells (Treg and MDSC).…”