Medical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.
Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2021-002460.
High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.
IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.
Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in ×LysM mice.
Our therapeutic vaccination protocol elicits a strong tumor-specific CD8 T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8 T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in ×LysM but not cre-negative control mice, while no differences in the vaccine-induced CD8 T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages.
IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections.
高血清白细胞介素 (IL-6) 水平可能通过调节肿瘤微环境中的髓样细胞导致对免疫疗法的耐药性。IL-6 信号通路阻断已在癌症中进行了测试，但由于这种炎症性细胞因子具有多种作用，因此这种治疗并非总是有效。
在 IL-6 介导的免疫治疗耐药 TC-1 肿瘤模型 (TC-1.IL-6) 和免疫治疗敏感的 TC-1 中应用 IL-6 和 IL-6R 阻断。
研究了对治疗性疫苗诱导的肿瘤消退、复发和存活的影响，以及对肿瘤微环境中的 T 细胞和髓样细胞的影响。在 ×LysM 小鼠中研究了治疗条件下巨噬细胞中 IL-6 信号的作用。
我们的治疗性疫苗方案引发了强烈的肿瘤特异性 CD8 T 细胞反应，导致肿瘤内 T 细胞浸润增加，并招募了杀瘤巨噬细胞。IL-6 信号通路阻断加剧了肿瘤生长，表现在治疗性疫苗后完全消退的病例减少，复发的病例增多，尤其是在 TC-1.IL-6 荷瘤小鼠中。早期 IL-6 信号通路阻断部分抑制了疫苗诱导的 CD8 T 细胞反应的发展。然而，主要机制是治疗诱导的肿瘤消退过程中巨噬细胞的功能障碍。在 ×LysM 但不是 cre-阴性对照小鼠中，治疗效果受损，而这些小鼠之间的疫苗诱导的 CD8 T 细胞反应没有差异。IL-6 信号通路阻断导致抑制性细胞因子信号转导 3 的表达减少，这对于巨噬细胞中有效的 M1 型功能至关重要，并且信号调节蛋白 alpha 的表达增加。
IL-6 信号通路对于免疫治疗诱导的肿瘤组织破坏情况下的巨噬细胞功能至关重要，这与感染中描述的 IL-6 信号的急性炎症功能一致。
