Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
J Immunother Cancer. 2019 Jan 29;7(1):21. doi: 10.1186/s40425-019-0503-6.
Transient depletion of CD4 T cells results in tumor suppression and survival benefit in murine models; however, the tumor progression and recurrence still occur over more long-term monitoring of mice. Thus, we explored an additional strategy to enhance endogenous immune responses by an alarmin, high mobility group nucleosome binding protein 1 (HMGN1).
The anti-tumor effects of HMGN1, anti-CD4 depleting antibody, and their combined treatment were monitored in the Colon26 or the B16F10 subcutaneous murine models. The tumor-infiltrating CD8 T cell proliferation, differentiation, exhaustion, and its gene expression were determined by flow cytometry, transcriptome analysis, and quantitative real-time PCR.
Our results show that a systemic administration of low doses of HMGN1 with an anti-CD4 depleting antibody (HMGN1/αCD4) promoted expansion of CD8 T cell populations (e.g. CD137 PD-1 and CD44 PD-1), recruited CCR7 migratory dendritic cells to the tumor, and reduced co-inhibitory molecules (e.g. PD-1, LAG-3, and TIM-3) to counteract CD8 T cell exhaustion.
The HMGN1/αCD4 treatment expanded effector CD8 T cells and prolonged their anti-tumor activities by rescuing them from exhaustion, thus resulting in tumor regression and even rejection in long-term monitored mice.
在小鼠模型中，CD4 T 细胞的短暂耗竭可导致肿瘤抑制和生存获益；然而，在对小鼠进行更长期的监测时，肿瘤仍会进展和复发。因此，我们探索了一种通过警报素高迁移率族核小体结合蛋白 1（HMGN1）增强内源性免疫反应的额外策略。
在 Colon26 或 B16F10 皮下小鼠模型中监测 HMGN1、抗 CD4 耗竭抗体及其联合治疗的抗肿瘤作用。通过流式细胞术、转录组分析和定量实时 PCR 测定肿瘤浸润 CD8 T 细胞的增殖、分化、耗竭及其基因表达。
我们的结果表明，低剂量 HMGN1 与抗 CD4 耗竭抗体（HMGN1/αCD4）联合全身给药可促进 CD8 T 细胞群体的扩增（例如 CD137 PD-1 和 CD44 PD-1），募集 CCR7 迁移树突状细胞到肿瘤，并减少共抑制分子（例如 PD-1、LAG-3 和 TIM-3）以抵抗 CD8 T 细胞耗竭。
HMGN1/αCD4 治疗通过从耗竭中挽救效应 CD8 T 细胞，从而扩大效应 CD8 T 细胞并延长其抗肿瘤活性，导致肿瘤消退甚至在长期监测的小鼠中被排斥。
