作者
Ronglai Shen,Michael A. Postow,Matthew Adamow,Arshi Arora,Margaret Hannum,Colleen Anne Maher,Phillip Wong,Michael A. Curran,Travis J. Hollmann,Liwei Jia,Hikmat Al-Ahmadie,Niamh M. Keegan,Samuel A. Funt,Gopa Iyer,Jonathan E. Rosenberg,Dean F. Bajorin,Paul B. Chapman,Alexander N. Shoushtari,Allison S. Betof,Parisa Momtaz,Taha Merghoub,Jedd D. Wolchok,Katherine S. Panageas,Margaret K. Callahan
摘要
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.