Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital and Institute, Haidian District, Beijing, China.
Department of General Surgery 1, Affiliated Hospital of Chengde Medical College, Chengde, China.
Cancer Immunol Res. 2018 Nov;6(11):1401-1416. doi: 10.1158/2326-6066.CIR-17-0630. Epub 2018 Oct 3.
Checkpoint blockade therapy triggers tumor-specific immune responses in a variety of cancer types. We presumed that rectal cancer patients could have become sensitive to immunotherapy after receiving neoadjuvant chemoradiotherapy (nCRT). In this study, we report immune alternation in post-nCRT patients compared with pretreatment conditions from gene-expression omnibus (GEO) data. Whole-exome sequencing of 14 locally advanced rectal cancer (LARC) patient samples showed that nCRT induced new mutations compared with the paired pretreatment biopsies, evidenced by appearance of a neoantigen landscape. An association was identified between mutation burden and enrichment of immune activation-related pathways. Animal experiment results further demonstrated that radiotherapy enhanced the efficacy of anti-PD-1. Mutation burden and the neoantigens of LARC patients were associated with response to nCRT. The mRNA expression profiling of 66 pretreatment biopsy samples from LARC patients showed that immune activation-related pathways were enriched in response to nCRT PD-L1 expression was negatively correlated with disease-free survival in the CD8-low expression patient group who received nCRT in a cohort of 296 samples. Thus, nCRT was able to alter immune function in LARC patients, which may be associated with the appearance of neoantigens. Neoantigens could make rectal cancer patients potential candidates to receive checkpoint blockade immunotherapy, and mutation burden could be a useful biomarker to stratify patients into responding and nonresponding groups for immunotherapy. .
检查点阻断疗法在多种癌症类型中引发肿瘤特异性免疫反应。我们推测，接受新辅助放化疗（nCRT）后，直肠癌患者可能对免疫疗法变得敏感。在这项研究中，我们根据基因表达综合数据库（GEO）的数据，报告了 nCRT 后患者与治疗前相比的免疫变化。对 14 例局部晚期直肠癌（LARC）患者样本进行全外显子测序，结果表明 nCRT 与配对的预处理活检相比诱导了新的突变，这一点从新抗原景观的出现就可以证明。突变负荷与免疫激活相关途径的富集之间存在关联。动物实验结果进一步表明，放疗增强了抗 PD-1 的疗效。LARC 患者的突变负荷和新抗原与 nCRT 反应相关。66 例 LARC 患者的 66 例预处理活检样本的 mRNA 表达谱分析显示，nCRT 应答中富集了与免疫激活相关的途径，在接受 nCRT 的 296 例样本的 CD8-低表达患者亚组中，nCRT 与 PD-L1 表达呈负相关，与无病生存相关。因此，nCRT 能够改变 LARC 患者的免疫功能，这可能与新抗原的出现有关。新抗原可能使直肠癌患者成为接受检查点阻断免疫治疗的潜在候选者，而突变负荷可能是将患者分层为免疫治疗应答和无应答组的有用生物标志物。
