TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma
TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma
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DOI：
10.1182/blood-2018-01-825265
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发表时间：
2018-10-18
期刊：
影响因子：
20.3
通讯作者：
Smyth, Mark J.
中科院分区：
文献类型：
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作者：
Guillerey, Camille;Harjunpaeae, Heidi;Smyth, Mark J.
基于免疫的疗法有望治疗多发性骨髓瘤（MM），但到目前为止，靶向程序性细胞死亡蛋白1的免疫检查点阻断剂尚未被证明在这种疾病中作为单一药物有效。T细胞免疫球蛋白和ITIM结构域（TIGIT）是已知负调节T细胞功能的另一种免疫检查点受体。在这项研究中，我们研究了TIGIT阻断释放针对MM的免疫应答的治疗潜力。我们观察到，在小鼠和人类中，MM进展与CD 8（+）T细胞上的高水平TIGIT表达相关。来自MM患者的TIGIT 1 CD 8（+）T细胞表现出功能失调的表型，其特征在于增殖降低并且不能响应于抗CD 3/CD 28/CD 2或骨髓瘤抗原刺激而产生细胞因子。此外，当用Vk* MYC小鼠MM细胞攻击时，TIGIT缺陷型小鼠显示与降低的肿瘤负荷和延长的存活相关的血清单克隆免疫球蛋白水平降低，表明TIGIT限制抗骨髓瘤免疫应答。重要的是，使用单克隆抗体阻断TIGIT增加了MM患者CD 8（+）T细胞的效应子功能并抑制MM发展。总之，我们的数据为TIGIT在MM中的免疫抑制作用提供了证据，并支持开发用于治疗MM患者的TIGIT阻断策略。
Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far, immune checkpoint blockade targeting programmed cell death protein 1 has not proven effective as single agent in this disease. T-cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T-cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8(+) T cells. TIGIT1 CD8(+) T cells from MM patients exhibited a dysfunctional phenotype characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk* MYC mouse MM cells, TIGIT-deficient mice showed decreased serum monoclonal immunoglobulin protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits antimyeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies increased the effector function of MM patient CD8(+) T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT-blocking strategies for the treatment of MM patients.