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
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.
Br J Cancer. 2025 Sep 2. doi: 10.1038/s41416-025-03137-8.
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.
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).
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.
These findings highlight the potential of MDM infiltration as a predictive biomarker for ICI response in metastatic melanoma.
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。
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。
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。
这些发现突出了MDM浸润作为转移性黑色素瘤ICI反应预测生物标志物的潜力。
