肿瘤微环境
免疫系统
癌相关成纤维细胞
癌症研究
生物
肿瘤浸润淋巴细胞
黑色素瘤
组织微阵列
间质细胞
细胞毒性T细胞
基质
病理
成纤维细胞活化蛋白
川地68
淋巴结
川地163
免疫检查点
癌症
医学
免疫学
免疫疗法
免疫组织化学
巨噬细胞
生物化学
遗传学
体外
作者
David G Su,David A. Schoenfeld,Wael Ibrahim,Raysa Cabrejo,Dijana Djureinovic,Raymond P. Baumann,David L. Rimm,Sajid Khan,Ruth Halaban,Harriet M. Kluger,Kelly Olino,Anjela Galan,James Clune
标识
DOI:10.1136/jitc-2023-008646
摘要
Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies.We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)).We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival.Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.
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