Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3⁺CD8⁺ T cell population. Patients with melanoma with a LAG⁺ immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG⁻ immunotype (P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG⁺ immunotype was significantly associated with response (P = 0.007), survival (P < 0.001), and progression-free survival (P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG⁺ immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG⁺ immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation.

免疫检查点阻断抗体是癌症治疗的基石；然而，它们仅使一部分患者受益，并且缺乏指导免疫检查点阻断 (ICB) 治疗选择的生物标志物。我们设计了这项研究来确定 ICB 治疗患者临床结果的血液相关性。我们使用多参数流式细胞术对 188 名 ICB 治疗的黑色素瘤患者进行了免疫分析，以表征治疗前外周血中的免疫细胞。将监督统计学习方法应用于发现队列以对表型进行分类并确定它们与生存和治疗反应的关联。我们确定了三种不同的免疫表型（免疫型），部分由 LAG-3 ⁺ CD8 ^{+的存在定义}T细胞群。^{LAG +}免疫型黑色素瘤患者ICB 后的预后较差，中位生存期为 22.2 个月，而 LAG ^-免疫型患者为 75.8 个月（P = 0.031）。一个由 94 名 ICB 治疗的尿路上皮癌患者组成的独立队列用于验证，其中 LAG ⁺免疫型与反应 ( P = 0.007)、生存期 ( P < 0.001) 和无进展生存期 ( P = 0.004) 显着相关。多变量 Cox 回归和分层分析进一步表明 LAG ⁺与已知的临床预后标志物和先前描述的 ICB、PD-L1 临床活性和肿瘤突变负荷标志物相比，免疫型是结果的独立标志物。预处理外周血 LAG ⁺免疫型检测不太可能从 ICB 中受益的患者，并提出了一种确定可操作免疫靶点的策略以供进一步研究。