IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-β, Collagen Type I, and PD-L1/PD-1
IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-β, Collagen Type I, and PD-L1/PD-1
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DOI：
10.4049/jimmunol.1800717
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发表时间：
2019-02-01
影响因子：
4.4
通讯作者：
Loskog, Angelica
中科院分区：
文献类型：
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作者：
Eriksson, Emma;Milenova, Ioanna;Loskog, Angelica
IL-6在癌症发病过程中发挥作用，其作用途径是与参与间质形成的蛋白有关，并通过与tgf - β一起驱动髓样抑制细胞的分化而进行免疫抑制。因此，抑制肿瘤微环境中的IL-6信号可能会限制结缔组织增生和骨髓抑制细胞分化。CD40信号传导可以进一步逆转骨髓细胞向抗肿瘤活性表型的分化。因此，同时使用IL-6阻断和CD40刺激可能会倾斜肿瘤微环境，以促进抗肿瘤免疫反应。在本文中，我们评估了LOAd713的机制，LOAd713是一种溶瘤腺病毒，旨在阻断IL-6R信号，并通过三聚体膜结合异亮氨酸拉链（TMZ） CD40L激活髓细胞。感染load713的胰腺癌细胞被肿瘤溶解杀死，而感染星状细胞可减少参与基质形成的因子，包括tgf - β -1和i型胶原。病毒感染可阻止IL-6/ gf - csf介导的髓样抑制因子分化，但不能阻止CD163巨噬细胞分化，而感染树突状细胞可导致成熟标志物上调，包括CD83、CD86、IL-12p70和ifn - γ。此外，IL-6R阻断可阻止程序性死亡配体1 （PD-L1）和PD-1在受刺激树突状细胞上的上调。这些结果表明，LOAd713可以杀死感染的肿瘤细胞，并具有通过TMZ-CD40L和IL-6R阻断刺激星状细胞和髓样抑制因子影响肿瘤微环境的能力。小鼠TMZ-CD40L基因转移在动物模型中延长存活时间。LOAd713可能是与IL-6信号相关的癌症（如胰腺癌）的一种有趣的治疗选择。
IL-6 plays a role in cancer pathogenesis via its connection to proteins involved in the formation of desmoplastic stroma and to immunosuppression by driving differentiation of myeloid suppressor cells together with TGF-beta. Inhibition of IL-6 signaling in the tumor microenvironment may, thus, limit desmoplasia and myeloid suppressor cell differentiation. CD40 signaling can further revert myeloid cell differentiation toward antitumor active phenotypes. Hence, the simultaneous use of IL-6 blockade with CD40 stimuli may tilt the tumor microenvironment to promote antitumor immune responses. In this paper, we evaluated the mechanisms of LOAd713, an oncolytic adenovirus designed to block IL-6R signaling and to provide myeloid cell activation via a trimerized membrane-bound isoleucine zipper (TMZ) CD40L. LOAd713-infected pancreatic cancer cells were killed by oncolysis, whereas infection of stellate cells reduced factors involved in stroma formation, including TGF-beta-1 and collagen type I. Virus infection prevented IL-6/GM-CSF-mediated differentiation of myeloid suppressors, but not CD163 macrophages, whereas infection of dendritic cells led to upregulation of maturation markers, including CD83, CD86, IL-12p70, and IFN-gamma. Further, IL-6R blockade prevented upregulation of programed death ligand 1 (PD-L1) and PD-1 on the stimulated dendritic cells. These results suggest that LOAd713 can kill infected tumor cells and has the capacity to affect the tumor microenvironment by stimulating stellate cells and myeloid suppressors with TMZ-CD40L and IL-6R blockade. Gene transfer of murine TMZ-CD40L prolonged survival in an animal model. LOAd713 may be an interesting therapeutic option for cancers connected to IL-6 signaling, such as pancreatic cancer.