mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers.
mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers.
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mTOR 通路基因突变可预测多种癌症对免疫检查点抑制剂的反应
DOI：
10.1186/s12967-022-03436-1
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发表时间：
2022-05-31
影响因子：
7.4
通讯作者：
Han, Baohui
中科院分区：
文献类型：
--
作者：
Cheng, Lei;Wang, Yanan;Qiu, Lixin;Chang, Yuanyuan;Lu, Haijiao;Liu, Chenchen;Zhang, Bo;Zhou, Yan;Bai, Hao;Xiong, Liwen;Zhong, Hua;Nie, Wei;Han, Baohui
mTOR 通路已知可促进癌症恶性并影响癌症免疫，但其在免疫检查点抑制剂 (ICI) 治疗中的作用尚不清楚。使用纪念斯隆-凯特琳癌症中心 (MSKCC) 数据集，我们提取了 1661 名接受 ICI 的癌症患者的 mTOR 通路基因突变，用于逐步 Cox 回归。我们将逐步 Cox 回归产生的基因特征突变与 1661 名患者的生存率联系起来。从 6 个队列中收集了其他 553 名接受 ICI 治疗的患者进行验证。我们还在未接受 ICI 治疗的患者中进行了这种生存关联，其中 MSKCC 作为发现 (n = 2244)，并通过癌症基因组图谱 (TCGA) 作为验证 (n = 763)。使用 TCGA 和 IMvigor210 试验的转录组图谱进行通路富集分析，以研究潜在机制。我们通过逐步 Cox 回归发现了 8 个参与 mTOR 通路的基因，包括 FGFR2、PIK3C3、FGFR4、FGFR1、FGF3、AKT1、mTOR 和 RPTOR（n = 1661）。在发现 (n = 1661) 和验证 (n = 553) 中，8 基因特征突变与 ICI 治疗患者的更好生存相关，这与肿瘤突变负荷 (TMB) 无关，主要归因于错义突变。在未接受 ICI 治疗的患者中未观察到这种生存相关性。有趣的是，8 个基因特征的突变与 TMB 和 PD1/PD-L1 表达增加有关。免疫学上，mTOR 通路中存在这种突变特征时，参与抗肿瘤免疫反应的通路丰富，导致免疫效应细胞（例如 CD8+T 细胞、NK 细胞和 M1 巨噬细胞）的浸润增加，但免疫抑制性 M2 巨噬细胞的浸润减少。这些结果表明，mTOR 通路基因突变可以预测多种癌症在 ICI 治疗后获得更好的生存期，这可能是因为它与增强的抗肿瘤免疫力相关。有必要进行更大规模的研究来验证我们的发现。在线版本包含可在 10.1186/s12967-022-03436-1 获取的补充材料。
mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. Using Memorial Sloan-Kettering Cancer Center dataset (MSKCC), we extracted mTOR pathway gene mutations for stepwise Cox regression in 1661 cancer patients received ICI. We associated the mutation of the gene signature resulted from the stepwise Cox regression with the 1661 patients’ survival. Other 553 ICI-treated patients were collected from 6 cohorts for validation. We also performed this survival association in patients without ICI treatment from MSKCC as discovery (n = 2244) and The Cancer Genome Atlas (TCGA) as validation (n = 763). Pathway enrichment analysis were performed using transcriptome profiles from TCGA and IMvigor210 trial to investigate the potential mechanism. We identified 8 genes involved in mTOR pathway, including FGFR2, PIK3C3, FGFR4, FGFR1, FGF3, AKT1, mTOR, and RPTOR, resulted from stepwise Cox regression in discovery (n = 1661). In both discovery (n = 1661) and validation (n = 553), the mutation of the 8-gene signature was associated with better survival of the patients treated with ICI, which was independent of tumor mutation burden (TMB) and mainly attributed to the missense mutations. This survival association was not observed in patients without ICI therapy. Intriguingly, the mutation of the 8-gene signature was associated with increased TMB and PD1/PD-L1 expression. Immunologically, pathways involved in anti-tumor immune response were enriched in presence of this mutational signature in mTOR pathway, leading to increased infiltration of immune effector cells (e.g., CD8 + T cells, NK cells, and M1 macrophages), but decreased infiltration of immune inhibitory M2 macrophages. These results suggested that mTOR pathway gene mutations were predictive of better survival upon ICI treatment in multiple cancers, likely by its association with enhanced anti-tumor immunity. Larger studies are warranted to validate our findings. The online version contains supplementary material available at 10.1186/s12967-022-03436-1.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
--
作者：
He Y;Wang X
通讯作者：
Wang X
DOI：
10.1126/science.aan5951
发表时间：
2018-02-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Miao D;Margolis CA;Gao W;Voss MH;Li W;Martini DJ;Norton C;Bossé D;Wankowicz SM;Cullen D;Horak C;Wind-Rotolo M;Tracy A;Giannakis M;Hodi FS;Drake CG;Ball MW;Allaf ME;Snyder A;Hellmann MD;Ho T;Motzer RJ;Signoretti S;Kaelin WG Jr;Choueiri TK;Van Allen EM
通讯作者：
Van Allen EM
影响因子：
16
作者：
Düvel K;Yecies JL;Menon S;Raman P;Lipovsky AI;Souza AL;Triantafellow E;Ma Q;Gorski R;Cleaver S;Vander Heiden MG;MacKeigan JP;Finan PM;Clish CB;Murphy LO;Manning BD
通讯作者：
Manning BD
影响因子：
64.8
作者：
Mariathasan S;Turley SJ;Nickles D;Castiglioni A;Yuen K;Wang Y;Kadel EE III;Koeppen H;Astarita JL;Cubas R;Jhunjhunwala S;Banchereau R;Yang Y;Guan Y;Chalouni C;Ziai J;Şenbabaoğlu Y;Santoro S;Sheinson D;Hung J;Giltnane JM;Pierce AA;Mesh K;Lianoglou S;Riegler J;Carano RAD;Eriksson P;Höglund M;Somarriba L;Halligan DL;van der Heijden MS;Loriot Y;Rosenberg JE;Fong L;Mellman I;Chen DS;Green M;Derleth C;Fine GD;Hegde PS;Bourgon R;Powles T
通讯作者：
Powles T