CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer.
CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer.
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DOI：
10.1016/j.celrep.2016.05.058
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发表时间：
2016-06-21
期刊：
影响因子：
8.8
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
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作者：
Byrne KT;Vonderheide RH
肿瘤免疫治疗对T细胞浸润较强的肿瘤更有效，但将主动免疫抑制的无T细胞肿瘤转化为能够招募T细胞的肿瘤的机制仍不完全清楚。在这里，使用基因工程的小鼠胰腺导管腺癌(PDA)模型，我们证明了单剂激动型CD40抗体联合化疗使PDA容易受到T细胞依赖的破坏，并增强了持久缓解。CD40刺激引起肿瘤中T细胞的克隆性增殖，但化疗的加入优化了髓系激活和T细胞功能。尽管最近的数据强调了在癌症免疫中对天然传感器的需求，但这些典型的途径-包括TLRs、炎症体和I型干扰素/刺激物-在调节CD40/化疗的疗效方面没有发挥作用。因此，CD40在肿瘤微环境的免疫转化中起着非冗余机制的作用。我们的数据为新启动的CD40/化疗在PDA中的临床试验提供了理论依据。免疫学上的“冷”肿瘤缺乏T细胞，对免疫治疗反应迟钝。伯恩和冯德海德表明，CD40刺激结合化疗，可以将冷肿瘤转化为T细胞渗透和破坏的部位，并具有持久的反应。功能性免疫反应独立于先天免疫感受器，在其他环境中很重要。
Cancer immunotherapies are more effective in tumors with robust T cell infiltrates, but mechanisms to convert T cell-devoid tumors with active immunosuppression to those capable of recruiting T cells remain incompletely understood. Here, using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDA), we demonstrate that a single dose of agonistic CD40 antibody with chemotherapy rendered PDA susceptible to T cell-dependent destruction and potentiated durable remissions. CD40 stimulation caused a clonal expansion of T cells in the tumor, but the addition of chemotherapy optimized myeloid activation and T cell function. Although recent data highlights the requirement for innate sensors in cancer immunity, these canonical pathways – including TLRs, inflammasome, and Type I interferon/STING – played no role in mediating the efficacy of CD40/chemotherapy. Thus, CD40 functions as a non-redundant mechanism to convert the tumor microenvironment immunologically. Our data provide a rationale for a newly initiated clinical trial of CD40/chemotherapy in PDA. Immunologically ‘cold’ tumors lack T cells and are hyporesponsive to immunotherapies. Byrne and Vonderheide show that CD40 stimulation, with chemotherapy, converts a ‘cold’ tumor to a site of T cell infiltration and destruction, with durable responses. Functional immune responses are independent of innate immune sensors important in other settings.