Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.
Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.
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DOI：
10.1158/0008-5472.can-13-3583
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Linden J
中科院分区：
文献类型：
--
作者：
Cekic C;Day YJ;Sag D;Linden J
肿瘤微环境中高浓度的腺苷抑制抗肿瘤细胞毒性淋巴细胞反应。尽管 T 细胞表达抑制性腺苷 A2A 受体 (A2AR)，可抑制其激活并抑制肿瘤的免疫杀伤，但骨髓细胞 A2AR 在抑制肿瘤免疫反应中的作用仍有待研究。在这项研究中，我们发现，在选择性缺乏髓系 A2AR 的 Adora2af/f–LysMCre+/- 小鼠中，移植的同基因 B16F10 黑色素瘤或 Lewis 肺癌细胞的生长减慢。黑色素瘤生长减少与肿瘤相关巨噬细胞中 MHCII 和 IL-12 表达显着增加有关，并且与肿瘤相关巨噬细胞、树突状细胞和 Ly6C+ 或 Ly6G+ 骨髓源性抑制细胞中 IL-10 表达减少 > 90% 相关。 A2AR 的髓系缺失显着增加了肿瘤相关 T 细胞和 NK 细胞上 CD44 的表达。荷瘤小鼠中 CD8+ T 细胞或 NK 细胞的耗竭表明，这两种细胞类型最初都有助于减缓缺乏骨髓 A2A 受体的小鼠中黑色素瘤的生长，但 CD8+ T 细胞介导的肿瘤抑制作用更为持久。骨髓选择性 A2AR 缺失显着减少表达荧光素酶（用于体内追踪）和卵清蛋白（作为模型抗原）的黑色素瘤的肺转移。转移减少与肺浸润中 NK 细胞和抗原特异性 CD8+ T 细胞的数量和活化增加有关。总体而言，研究结果表明，骨髓细胞 A2AR 具有直接的骨髓抑制作用，间接有助于抑制原发性和转移性肿瘤微环境中的 T 细胞和 NK 细胞。结果表明，肿瘤相关骨髓细胞，包括巨噬细胞、DC和MDSC都表达免疫抑制性A2AR，它们是腺苷受体阻滞剂增强肿瘤免疫杀伤的潜在靶点。
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.