Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
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DOI：
10.1158/2326-6066.cir-16-0159
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发表时间：
2016-12
影响因子：
10.1
通讯作者：
Teague RM
中科院分区：
文献类型：
--
作者：
Klevorn LE;Berrien-Elliott MM;Yuan J;Kuehm LM;Felock GD;Crowe SA;Teague RM
白细胞介素-2（IL-2）是最早用于癌症免疫治疗的试剂之一，因为它能够支持肿瘤反应性T细胞的存活和功能。然而，用IL 2治疗伴随着脱靶毒性和患者的低应答率。在小鼠模型中，当IL 2作为细胞因子/抗体复合物（IL 2c）施用时，这些问题在很大程度上被克服。该复合物具有较长的血清半衰期，并且可以被设计用于优先向感兴趣的特定细胞递送细胞因子。早期研究表明，IL 2c可以通过激活肿瘤反应性CD 8 + T细胞来增强小鼠的抗肿瘤免疫。但这种功能性T细胞通常局限于肿瘤微环境中，而非无反应的耐受性T细胞最终被细胞凋亡消除，这是癌症免疫治疗成功的主要障碍。我们发现，IL 2c治疗将肿瘤特异性CD 8 + T细胞从已建立的耐受状态中拯救出来，为荷瘤小鼠提供了有效的免疫治疗。转录因子T-bet的表达是驱动肿瘤内IFNγ产生和IL 2c拯救的T细胞的效应活性所必需的。此外，IL 2c促进人源化荷瘤小鼠中人CD 4+和CD 8 + T细胞中的T-bet表达，但也增加Foxp 3+调节性T细胞的频率。我们的研究揭示了IL 2c作为一种强大的免疫抑制剂的新作用，能够逆转肿瘤反应性T细胞的耐受性，并提供了第一个证据表明IL 2c在体内影响人类T细胞，突出了调节人类抗肿瘤免疫应答的翻译潜力。
Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability to support the survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity and low response rates in patients. In mouse models, these issues are largely overcome when IL2 is administered as a cytokine/antibody complex (IL2c). The complex has a longer serum half-life and can be designed for preferential cytokine delivery to specific cells of interest. Early studies showed IL2c could boost antitumor immunity in mice by activating tumor-reactive CD8+ T cells. But such functional T cells are often limited in the tumor microenvironment, where instead unresponsive tolerant T cells are eventually eliminated by apoptosis, representing a major obstacle to the success of cancer immunotherapy. We found that IL2c treatment rescued tumor-specific CD8+ T cells from a state of established tolerance, providing effective immunotherapy in tumor-bearing mice. Expression of the transcription factor T-bet was necessary to drive intratumoral IFNγ production and effector activity by T cells rescued with IL2c. Furthermore, IL2c promoted T-bet expression in human CD4+ and CD8+ T cells in humanized tumor-bearing mice, but also increased the frequency of Foxp3+ regulatory T cells. Our study reveals a novel role for IL2c as a powerful immunotherapeutic reagent capable of reversing tolerance in tumor-reactive T cells, and provides the first evidence that IL2c influences human T cells in vivo, highlighting the translational potential to modulate human antitumor immune responses.