TY - JOUR
T1 - LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade
AU - Shen, Ronglai
AU - Postow, Michael A.
AU - Adamow, Matthew
AU - Arora, Arshi
AU - Hannum, Margaret
AU - Maher, Colleen
AU - Wong, Phillip
AU - Curran, Michael A.
AU - Hollmann, Travis J.
AU - Jia, Liwei
AU - Al-Ahmadie, Hikmat
AU - Keegan, Niamh
AU - Funt, Samuel A.
AU - Iyer, Gopa
AU - Rosenberg, Jonathan E.
AU - Bajorin, Dean F.
AU - Chapman, Paul B.
AU - Shoushtari, Alexander N.
AU - Betof, Allison S.
AU - Momtaz, Parisa
AU - Merghoub, Taha
AU - Wolchok, Jedd D.
AU - Panageas, Katherine S.
AU - Callahan, Margaret K.
N1 - Publisher Copyright:
© 2021 The Authors, some rights reserved;
PY - 2021/8/25
Y1 - 2021/8/25
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.abf5107
DO - 10.1126/scitranslmed.abf5107
M3 - Article
C2 - 34433638
AN - SCOPUS:85114969545
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 608
M1 - eabf5107
ER -