POLE and Mismatch Repair Status, Checkpoint Proteins and Tumor-Infiltrating Lymphocytes in Combination, and Tumor Differentiation: Identify Endometrial Cancers for Immunotherapy.
POLE and Mismatch Repair Status, Checkpoint Proteins and Tumor-Infiltrating Lymphocytes in Combination, and Tumor Differentiation: Identify Endometrial Cancers for Immunotherapy.
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POLE 和错配修复状态、检查点蛋白和肿瘤浸润淋巴细胞的组合以及肿瘤分化：识别子宫内膜癌以进行免疫治疗
DOI：
10.3389/fonc.2021.640018
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发表时间：
2021
影响因子：
4.7
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Dong D;Lei H;Liu D;Bai H;Yang Y;Tang B;Li K;Liu J;Xu G;Xiao X
尽管聚合酶-β 1（POLE）突变和错配修复（MMR）缺陷型子宫内膜癌（EC）被认为是抗PD-1/PD-L1治疗的有希望的候选者，但仅选择这些患者可能会排除可能对这种治疗策略有潜在反应的其他患者，突出了需要额外的生物标志物以更好地选择患者。本研究旨在评价除POLE突变（POLEm）和MMR缺陷（MMRd）外，抗PD-1/PD-L1治疗的潜在预测生物标志物。我们对来自202个EC的POLE进行了下一代测序，并对来自这些EC的全切片载玻片上的MLH 1、MSH 2、MSH 6、PMS 2、CD 3、CD 8、PD-1和PD-L1进行了免疫组化。我们评估了POLEm和MMRd与临床病理特征、检查点蛋白表达和肿瘤浸润淋巴细胞（TIL）密度的相关性。还评估了这些免疫标志物的预后影响。POLEm、MMRd和高级别肿瘤表现出TIL水平升高。在MMRd和高级别EC中观察到PD-1和PD-L1表达增加。一个亚组的MMR熟练EC也具有增加的TIL密度，以及PD-1和PD-L1的阳性表达。此外，检查点蛋白的阴性表达和高密度的TIL组合与良好的预后相关。PD-1阻断的候选者可能超出POLEm和MMRd EC，可能需要考虑其他因素，如肿瘤分级以及TIL水平和检查点蛋白表达的组合，以更好地选择患者。
Although Polymerase-epsilon (POLE)-mutated and mismatch repair (MMR)-deficient endometrial cancers (ECs) are considered as promising candidates for anti-PD-1/PD-L1 therapy, selecting only these patients may exclude other patients who could potentially respond to this treatment strategy, highlighting the need of additional biomarkers for better patient selection. This study aims to evaluate potential predictive biomarkers for anti-PD-1/PD-L1 therapy in addition to POLE mutation (POLEm) and MMR deficiency (MMRd). We performed next generation sequencing for POLE from 202 ECs, and immunohistochemistry for MLH1, MSH2, MSH6, PMS2, CD3, CD8, PD-1 and PD-L1 on full-section slides from these ECs. We assessed the association of POLEm and MMRd with clinicopathologic features, expression of check point proteins, and density of tumor-infiltrating lymphocytes (TILs). Prognostic impact of these immune markers was also evaluated. POLEm, MMRd and high-grade tumors exhibited elevated level of TILs. Increased expression of PD-1 and PD-L1 was observed in MMRd and high-grade ECs. A subgroup of MMR proficient ECs also harbored increased density of TILs, and positive expression of PD-1 and PD-L1. In addition, negative expression of checkpoint proteins and high density of TILs in combination was associated with good prognosis. Candidates for PD-1 blockade may extend beyond POLEm and MMRd ECs, additional factors such as tumor grade, and combination of TILs levels and expression of checkpoint proteins may need to be considered for better patient selection.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
45.3
作者：
Ott, Patrick A.;Bang, Yung-Jue;Soria, Jean-Charles
通讯作者：
Soria, Jean-Charles
影响因子：
3.5
作者：
Church DN;Briggs SE;Palles C;Domingo E;Kearsey SJ;Grimes JM;Gorman M;Martin L;Howarth KM;Hodgson SV;NSECG Collaborators;Kaur K;Taylor J;Tomlinson IP
通讯作者：
Tomlinson IP
影响因子：
28.2
作者：
Llosa, Nicolas J.;Cruise, Michael;Housseau, Franck
通讯作者：
Housseau, Franck
DOI：
10.1093/jnci/dju402
发表时间：
2015-01
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Church DN;Stelloo E;Nout RA;Valtcheva N;Depreeuw J;ter Haar N;Noske A;Amant F;Tomlinson IP;Wild PJ;Lambrechts D;Jürgenliemk-Schulz IM;Jobsen JJ;Smit VT;Creutzberg CL;Bosse T
通讯作者：
Bosse T