免疫检查点
CTLA-4号机组
封锁
医学
易普利姆玛
无容量
免疫疗法
细胞毒性T细胞
癌症研究
免疫系统
PD-L1
T细胞
癌症
黑色素瘤
抗体
彭布罗利珠单抗
抗原
肿瘤微环境
肿瘤科
生物
免疫学
内科学
受体
体外
生物化学
作者
Oscar Krijgsman,Kristel Kemper,Julia Boshuizen,David W. Vredevoogd,Elisa A. Rozeman,Sofía Ibáñez Molero,Beaunelle de Bruijn,Paulien Cornelissen-Steijger,Aida Shahrabi,Martín Del Castillo Velasco-Herrera,Ji‐Ying Song,Maarten A. Ligtenberg,Roelof J.C. Kluin,Thomas Kuilman,Petra Ross‐Macdonald,John B.A.G. Haanen,David J. Adams,Christian U. Blank,Daniel S. Peeper
标识
DOI:10.1158/1078-0432.ccr-20-4218
摘要
Combining anti-PD-1 + anti-CTLA-4 immune-checkpoint blockade (ICB) shows improved patient benefit, but it is associated with severe immune-related adverse events and exceedingly high cost. Therefore, there is a dire need to predict which patients respond to monotherapy and which require combination ICB treatment.In patient-derived melanoma xenografts (PDX), human tumor microenvironment (TME) cells were swiftly replaced by murine cells upon transplantation. Using our XenofilteR deconvolution algorithm we curated human tumor cell RNA reads, which were subsequently subtracted in silico from bulk (tumor cell + TME) patients' melanoma RNA. This produced a purely tumor cell-intrinsic signature ("InTumor") and a signature comprising tumor cell-extrinsic RNA reads ("ExTumor").We show that whereas the InTumor signature predicts response to anti-PD-1, the ExTumor predicts anti-CTLA-4 benefit. In PDX, InTumorLO, but not InTumorHI, tumors are effectively eliminated by cytotoxic T cells. When used in conjunction, the InTumor and ExTumor signatures identify not only patients who have a substantially higher chance of responding to combination treatment than to either monotherapy, but also those who are likely to benefit little from anti-CTLA-4 on top of anti-PD-1.These signatures may be exploited to distinguish melanoma patients who need combination ICB blockade from those who likely benefit from either monotherapy.
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