替莫唑胺剂量的调节对 T 细胞对免疫检查点抑制的反应有差异影响。

Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition.

机构信息

Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, Florida.

出版信息

Neuro Oncol. 2019 Jun 10;21(6):730-741. doi: 10.1093/neuonc/noz015.

DOI:10.1093/neuonc/noz015

PMID:30668768

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6556847/

Abstract

BACKGROUND

The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM.

METHODS

Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models.

RESULTS

SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone.

CONCLUSION

The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.

摘要

背景

化疗引起的宿主免疫和肿瘤微环境的变化已被证明会以正反两方面影响免疫治疗的反应。替莫唑胺是治疗胶质母细胞瘤（GBM）最常用的化疗药物，其对免疫治疗的免疫反应的影响具有可变性。因此，我们旨在确定替莫唑胺的免疫调节作用，以影响实验性 GBM 中免疫检查点抑制的反应。

方法

在 GL261 和 KR158 鼠胶质母细胞瘤模型中，用低剂量（MD）替莫唑胺（25mg/kg×10 天）或标准剂量（SD）替莫唑胺（50mg/kg×5 天）治疗后，检测免疫检查点抑制的免疫功能和抗肿瘤疗效。

结果

SD 替莫唑胺治疗导致淋巴细胞中 T 细胞耗竭标志物如 LAG-3 和 TIM-3 的上调，而 MD 替莫唑胺则没有。当替莫唑胺治疗与程序性细胞死亡 1（PD-1）抗体治疗联合应用时，MD 替莫唑胺/PD-1 抗体组在肿瘤浸润淋巴细胞中观察到耗竭标志物减少，而 SD 替莫唑胺/PD-1 抗体组则没有。此外，在小鼠同源颅内胶质母细胞瘤模型中，PD-1 抗体治疗的生存优势被添加 SD 替莫唑胺治疗所阻断。然而，当 MD 替莫唑胺与 PD-1 抑制联合应用时，它保留了 PD-1 抗体治疗单独应用时所观察到的生存获益。