骨巨细胞瘤分泌的 OSM 和 Nivolumab 对 TRAIL 诱导的软组织肉瘤非白细胞细胞亚群中细胞毒性 T 细胞比例和敏感性的影响。

Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas.

机构信息

Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy.

3rd Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.

出版信息

Pharmacology. 2023;108(3):274-285. doi: 10.1159/000529811. Epub 2023 Mar 30.

DOI:10.1159/000529811

PMID:36996792

Abstract

INTRODUCTION

Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far.

METHODS

The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies.

RESULTS

The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma.

CONCLUSION

In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.

摘要

简介

软组织肉瘤（STS）是起源于间叶组织的恶性肿瘤。晚期和转移性 STS 患者的总体生存率较低，治疗选择相对有限。肿瘤坏死因子样弱凋亡诱导因子（OSM）是一种多效细胞因子，在多种癌症类型中表现出促肿瘤和抗肿瘤特性。然而，OSM 在 STS 中的作用尚未阐明。此外，迄今为止尚未进行 OSM 与抗 PD-1 治疗联合的潜在增效作用的研究。

方法

本研究旨在确定体外给予 OSM 对从外周血和肿瘤组织分离的脂肪肉瘤、平滑肌肉瘤和黏液纤维肉瘤免疫细胞的影响，以及 OSM 和纳武利尤单抗治疗这些 STS 的潜在协同作用。我们设计了一项队列研究，以探索我们目标 STS 中的新型组织学驱动治疗方法。从 STS 患者的外周血和肿瘤中分离免疫细胞，并用治疗性单克隆抗体培养后，用流式细胞术评估免疫细胞的比例和表型。

结果

外周血 CD45+细胞的比例不受 OSM 影响，但受纳武利尤单抗显著增加，而两种治疗方法均对 CD8+T 细胞有影响。在肿瘤组织中，CD8+T 细胞和 CD45‒TRAIL+细胞培养物受纳武利尤单抗增强，并被 OSM 显著富集。我们的数据表明，OSM 可能在平滑肌肉瘤、黏液纤维肉瘤和脂肪肉瘤的治疗中发挥作用。