ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma.
ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma.
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ERK1/2磷酸化可预测复发胶质母细胞瘤抗PD-1免疫治疗后的存活率。
DOI：
10.1038/s43018-021-00260-2
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发表时间：
2021-12
期刊：
影响因子：
22.7
通讯作者：
Sonabend AM
中科院分区：
文献类型：
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作者：
Arrieta VA;Chen AX;Kane JR;Kang SJ;Kassab C;Dmello C;Zhao J;Burdett KB;Upadhyayula PS;Lee-Chang C;Shilati J;Jaishankar D;Chen L;Gould A;Zhang D;Yuan J;Zhao W;Ling X;Burks JK;Laffleur B;Amidei C;Bruce JN;Lukas RV;Yamaguchi JT;Cieremans D;Rothschild G;Basu U;McCord M;Brat DJ;Zhang H;Cooper LAD;Zhang B;Sims P;Cloughesy TF;Prins R;Canoll P;Stupp R;Heimberger AB;Horbinski C;Iwamoto FM;Rabadan R;Sonabend AM
只有一部分复发性胶质母细胞瘤（rGBM）对抗pd -1免疫治疗有反应。之前，我们报道了30%对PD-1阻断有反应的rGBM中BRAF/PTPN11突变的富集。考虑到BRAF和PTPN11促进MAPK/ERK信号传导，我们研究了该途径的激活是否与rGBM中PD-1抑制剂的反应有关，包括没有BRAF/PTPN11突变的患者。本研究表明，在两个独立的rGBM患者队列中，ERK1/2磷酸化（p-ERK） （MAPK/ERK通路激活的标记物）的免疫组织化学可以预测PD-1佐剂阻断后的总生存率。单细胞rna测序和多重免疫荧光分析显示，p-ERK主要定位于肿瘤细胞，高p-ERK GBMs中含有肿瘤浸润性骨髓细胞和小胶质细胞，MHC II类及相关基因表达升高。这些发现表明，rGBM中的ERK1/2激活可预测对PD-1阻断的反应，并与不同的骨髓细胞表型相关。
Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.