Baseline immunosuppressive spatiotypes in adolescent and young adult melanoma patients treated with checkpoint immunotherapy

We compared the transcriptomic, genomic, and spatial cellular profiles of the tumor microenvironment (TME) in AYA and adult melanomas to determine the pathways associated with ICI outcomes in AYA patients. We identified two ICI-resistant spatiotypes of AYA melanoma with distinct stroma infiltrating lymphocytes (SILs) unique from adult TME; SILhigh subtype was enriched for regulatory T-cells in the peritumoral space and showed alternative checkpoint expression (e.g. TIM3, ICOS), while the SILlow subtype showed a lack of immune induction. We further established a novel YIM (young immunosuppressive melanoma) score for predicting ICI response for AYA patients and proposed personalized therapeutic strategies for the ICI-resistant subgroups.本研究比较了青少年与年轻成人（Adolescent and Young Adult, AYA）与成人黑色素瘤的肿瘤微环境（tumor microenvironment, TME）的转录组、基因组及空间细胞图谱，旨在明确与AYA患者免疫检查点抑制剂（immune checkpoint inhibitor, ICI）治疗结局相关的通路。本研究鉴定出两种存在于AYA黑色素瘤中的ICI耐药空间表型，其具有区别于成人TME的独特基质浸润淋巴细胞（stroma infiltrating lymphocytes, SILs）特征：SIL高表达亚型在瘤周区域富集调节性T细胞，并呈现出替代性免疫检查点表达谱（例如TIM3、ICOS）；而SIL低表达亚型则存在免疫诱导缺失现象。本研究进一步构建了用于预测AYA患者ICI治疗响应的新型青年免疫抑制黑色素瘤（young immunosuppressive melanoma, YIM）评分，并针对ICI耐药亚群提出了个性化治疗策略。