New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115; and.
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115; and
J Immunol. 2018 Jul 15;201(2):782-791. doi: 10.4049/jimmunol.1700850. Epub 2018 May 25.
Tumor hypoxia-driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A adenosine receptors (AR) on tumor-reactive effector T cells, but there remains a need for careful evaluation of the limiting factors and properties of AR blockade-enabled antitumor immunity. In studies of AR and/or AR gene-deficient mice, we found that AR deletion-but not AR deletion-liberates endogenous CD8 T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred AR, AR, or AR/AR tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by AR on CD8 T cells. Treatment with AR antagonist mimicked AR gene deletion in adoptive T cell immunotherapy. This therapeutic benefit of targeting AR was independent of the anatomical location of tumor growth. The enhanced antitumor reactivity also led to the eradication of established intracranial tumors, which was associated with mouse survival and the maintenance of long-lasting, tumor-specific immunological memory. The blockade of the AR on adoptively transferred T cells by synthetic AR antagonist led to higher levels of IFN-γ secretion by tumor-infiltrating CD8 T cells. These data clarify the mechanism of hypoxia-driven immunosuppression in the tumor microenvironment by AR on tumor-reactive CD8 T cells and show that selective AR antagonists can be effective in improving the outcomes of T cell-based immunotherapies. Demonstration of the T cell dose dependency of tumor rejection points to a major limitation of current cancer immunotherapies, in which the presence of sufficient numbers of tumor-reactive T cells in a patient is not known.
肿瘤缺氧驱动细胞外腺苷的积累被证明通过与肿瘤反应性效应 T 细胞上的免疫抑制性、细胞内 cAMP 升高的 A 腺苷受体 (AR) 相互作用，促进肿瘤逃逸，但仍需要仔细评估 AR 阻断增强抗肿瘤免疫的限制因素和特性。在 AR 和/或 AR 基因缺陷小鼠的研究中，我们发现 AR 缺失 - 而不是 AR 缺失 - 释放了针对弱免疫原性 MCA205 肉瘤的内源性 CD8 T 细胞抗肿瘤免疫。过继转移 AR、AR 或 AR/AR 肿瘤反应性 T 细胞的研究证实，肿瘤微环境中的免疫抑制是由 CD8 T 细胞上的 AR 介导的。AR 拮抗剂的治疗可模拟过继 T 细胞免疫治疗中的 AR 基因缺失。这种靶向 AR 的治疗益处独立于肿瘤生长的解剖位置。增强的抗肿瘤反应也导致了已建立的颅内肿瘤的根除，这与小鼠的存活和长期、肿瘤特异性免疫记忆的维持有关。通过合成 AR 拮抗剂对过继转移 T 细胞上的 AR 进行阻断，导致肿瘤浸润性 CD8 T 细胞中 IFN-γ分泌水平升高。这些数据阐明了 AR 在肿瘤反应性 CD8 T 细胞上通过肿瘤缺氧驱动的肿瘤微环境中免疫抑制的机制，并表明选择性 AR 拮抗剂可有效改善基于 T 细胞的免疫疗法的结果。肿瘤排斥的 T 细胞剂量依赖性的证明表明了当前癌症免疫疗法的一个主要限制，即患者中是否存在足够数量的肿瘤反应性 T 细胞尚不清楚。
