肿瘤微环境中的 CD47 限制了抗肿瘤 T 细胞免疫与放疗的协同作用。

CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy.

机构信息

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

出版信息

Cancer Res. 2014 Dec 1;74(23):6771-83. doi: 10.1158/0008-5472.CAN-14-0037-T. Epub 2014 Oct 8.

Abstract

Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8(+) T cells restored combinatorial efficacy. Furthermore, ablation of CD8(+) T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8(+) CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8(+) T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses.

摘要

尽管放疗技术取得了重大进展,提高了其在许多癌症治疗中的疗效,但拓宽正常组织毒性和恶性肿瘤破坏之间治疗窗口的一般策略仍具有重要价值。阻断 CD47 已被发现能为正常组织提供放射保护,同时增强肿瘤对放射的敏感性。在这里,我们报告阻断 CD47 能直接增强 CD8(+)T 细胞对肿瘤的免疫监视作用。阻断 CD47 联合放疗对 T 细胞缺陷小鼠的纤维肉瘤生长没有影响,而肿瘤特异性 CD8(+)T 细胞的过继转移恢复了联合疗效。此外,CD8(+)T 细胞的消融消除了免疫活性同种异体宿主的放射治疗反应。在体外,阻断靶细胞或效应细胞中的 CD47 足以增强抗原依赖性 CD8(+)CTL 介导的肿瘤细胞杀伤。在 CD47 缺陷的同基因宿主中,移植的 B16 黑色素瘤对放疗的敏感性增加了 50%,这表明微环境中的 CD47 表达足以限制肿瘤对放疗的敏感性。机制研究表明,在 CD47 缺陷的微环境中,细胞毒性 CD8(+)T 细胞浸润增加,与 T 细胞依赖性肿瘤内颗粒酶 B 的表达增加相关。相应地,在人类黑色素瘤中观察到 CD8(+)T 细胞浸润与 CD47 表达呈负相关。我们的研究结果表明,在放疗的背景下阻断 CD47 通过直接刺激 CD8(+)细胞毒性 T 细胞增强抗肿瘤免疫,有可能增加治愈反应。

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