RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
PTCH1 突变促进结直肠癌患者的抗肿瘤免疫和对免疫检查点抑制剂的反应
英文原题：PTCH1 mutation promotes antitumor immunity and the response to immune checkpoint inhibitors in colorectal cancer patients.
查看英文原题
PTCH1 mutation promotes antitumor immunity and the response to immune checkpoint inhibitors in colorectal cancer patients.
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中文摘要
免疫治疗已成为包括结直肠癌（CRC）在内的多种癌症的有效治疗策略，但仅有一部分MSI-H患者能从中获益。Patched1（PTCH1）是CRC中频繁发生改变的基因，其突变导致Hedgehog（Hh）信号通路失调。
在本研究中，我们基于单中心队列和多个癌症基因组数据集，评估了PTCH1突变与CRC免疫的关联。在21例入组患者中，基于WES分析，6例（28.6%）携带PTCH1突变。在CRC患者中，PTCH1突变亚组的持久临床获益率高于PTCH1野生型亚组（100% vs. 40%，P = 0.017）。
此外，携带PTCH1突变的患者获得了更长的无进展生存期（PFS，P = 0.037；HR，0.208）和总生存期（OS，P = 0.045；HR，0.185）。来自MSKCC的验证队列也证实了PTCH1突变与更好预后之间的相关性（P = 0.022；HR，0.290）。在机制上，多种抗肿瘤免疫特征在PTCH1突变肿瘤中比在PTCH1野生型肿瘤中富集程度更高。
此外，PTCH1突变肿瘤具有更高比例的CD8 + T细胞、活化NK细胞和M1型巨噬细胞浸润，以及癌症-免疫循环中多个步骤的基因特征升高。
值得注意的是，PTCH1突变与肿瘤突变负荷（TMB）、杂合性缺失评分和拷贝数变异负荷相关。我们的结果表明，PTCH1突变是预测CRC患者免疫治疗反应的潜在生物标志物。
展开英文摘要原文
Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling.
In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28. 6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0. 017).
In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0. 037; HR, 0. 208) and overall survival (OS, P = 0. 045; HR, 0. 185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0. 022; HR, 0. 290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors.
Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle.
Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden.
Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy.
论文信息
- 作者
- Wang Y、Chen H、Jiao X、Wu L、Yang Y、Zhang J、Wu L、Liu C
- 第一作者单位
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.China
- 通讯作者单位
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China. shenlin@bjmu.edu.cn.China
- 期刊
- Cancer immunology, immunotherapy : CII2022 Jan
- 原文标识
- PubMed 34028566 · DOI 10.1007/s00262-021-02966-9
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