抗程序性死亡蛋白1（Anti-PD-1）治疗反应与循环髓系细胞和T细胞亚群流入转移性黑色素瘤肿瘤微环境有关。

Anti-PD-1 treatment response is associated with the influx of circulating myeloid and T-cell subsets into the metastatic melanoma tumor microenvironment.

作者信息

Van Dam S, Krijgsman D, Küçükköse E, Verdonschot M E L, Amini M, Blokx W A M, Van Eijs M J M, Verheijden R J, Kranenburg O, Suijkerbuijk K P M, Leusen J H W, Vercoulen Y

机构信息

Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

出版信息

Br J Cancer. 2025 Sep 2. doi: 10.1038/s41416-025-03137-8.

DOI:10.1038/s41416-025-03137-8

PMID:40897819

Abstract

BACKGROUND

Immune checkpoint inhibition (ICI) significantly improves the survival of metastatic melanoma patients; however, a substantial proportion of patients does not respond to these breakthrough therapies.

METHODS

To improve our understanding of this response variability, we developed high-plex panels for protein imaging of a discovery cohort and validation with RNAseq analyses to examine myeloid and T-cell subsets in pre-anti-PD-1-treatment samples of 14 metastatic melanoma patients (7 responders and 7 non-responders).

RESULTS

We demonstrate that a higher abundance of circulating monocyte-derived macrophages (MDMs) and cytotoxic T-cell subsets in the tumor microenvironment (TME) at baseline distinguishes metastatic melanoma patients with a favorable response to anti-PD1 treatment from non-responders, who featured co-localization of suppressive macrophages (M2) and T-cells. Additionally, MDMs expressed high levels of immune checkpoints, and MDM infiltration into the TME was linked to both ICI response and survival.

CONCLUSION

These findings highlight the potential of MDM infiltration as a predictive biomarker for ICI response in metastatic melanoma.

摘要

背景

免疫检查点抑制（ICI）显著提高了转移性黑色素瘤患者的生存率；然而，相当一部分患者对这些突破性疗法没有反应。

方法

为了更好地理解这种反应变异性，我们开发了用于发现队列蛋白质成像的高倍体面板，并通过RNAseq分析进行验证，以检查14例转移性黑色素瘤患者（7例反应者和7例无反应者）抗PD-1治疗前样本中的髓系和T细胞亚群。

结果

我们证明，基线时肿瘤微环境（TME）中循环单核细胞衍生巨噬细胞（MDM）和细胞毒性T细胞亚群的丰度较高，可将对抗PD-1治疗有良好反应的转移性黑色素瘤患者与无反应者区分开来，无反应者的特征是抑制性巨噬细胞（M2）和T细胞共定位。此外，MDM表达高水平的免疫检查点，MDM浸润到TME与ICI反应和生存均相关。