肿瘤细胞治疗研究
英文原题：Predictors of Immune Checkpoint Blockade Response in dMMR Colorectal Cancer Using an Integrated Immune-Enhanced Multiomics Platform.
结合MSI定量的外显子组/转录组整合分析发现，MSI负荷和适应性免疫组库多样性可能是ICB治疗后应答和生存的潜在相关因素。这些发现提示基因组不稳定性、抗原识别多样性与免疫治疗获益之间存在机制性联系。
免疫检查点阻断（ICB）在转移性DNA错配修复缺陷（dMMR）结直肠癌中可诱导频繁且持久的缓解，但仍存在显著的分子异质性和耐药性。我们试图识别与抗PD-1治疗后临床结局相关的候选肿瘤及免疫相关生物标志物。
连续接受抗PD-1治疗的转移性dMMR结直肠癌患者（N = 39）通过经过验证的免疫增强外显子组和转录组平台进行了肿瘤分析。使用MSIsensor-pro将微卫星不稳定性（MSI）负荷量化为不稳定微卫星位点的百分比。评估了与客观缓解的关联，并使用Cox比例风险模型分析了无进展生存期（PFS）和总生存期（OS）。
较高的 MSI 负荷与客观缓解改善（P = 0.018）和生存改善相关。二分类 MSI 水平（Q2-4 对比 Q1）与更长的 PFS 相关[风险比（HR），0.18；95% 置信区间（CI），0.06-0.56；P = 0.003]和 OS 相关（HR，0.20；95% CI，0.07-0.58；P = 0.003），连续建模时结果相似。MSI 负荷与新抗原克隆性相关，但与新抗原负荷无关（R = 0.53，P = 0.01）。缓解者表现出显著更高的 T 细胞受体库多样性；T 细胞和 B 细胞受体多样性与生存均相关。尽管人类白细胞抗原（HLA）A、HLA-B 和 HLA-C 表达无预后意义，但 HLA-B*07:02 等位基因与最佳总体缓解相关。相反，免疫耗竭相关基因的过表达以及细胞毒性 T 细胞和NK 细胞耗竭表型与 ICB 耐药和更差预后相关。
PURPOSE: Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic deficient DNA mismatch repair (dMMR) colorectal cancer, yet substantial molecular heterogeneity and resistance remain. We sought to identify candidate tumor- and immune-related biomarkers associated with clinical outcomes following anti-PD-1 therapy. EXPERIMENTAL DESIGN: Consecutive patients with metastatic dMMR colorectal cancer (N = 39) treated with anti-PD-1 therapy underwent tumor profiling using a validated immune-enhanced exome and transcriptome platform. Microsatellite instability (MSI) burden was quantified as the percentage of unstable microsatellite loci using MSIsensor-pro. Associations with objective response were evaluated, and progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models. RESULTS: Higher MSI burden was associated with improved objective response (P = 0.018) and survival. The dichotomized MSI level (Q2-4 vs. Q1) was associated with longer PFS [hazard ratio (HR), 0.18; 95% confidence interval (CI), 0.06-0.56; P = 0.003] and OS (HR, 0.20; 95% CI, 0.07-0.58; P = 0.003), with similar results when modeled continuously. MSI burden correlated with neoantigen clonality but not burden (R = 0.53, P = 0.01). Responders exhibited significantly greater T-cell receptor repertoire diversity; both T- and B-cell receptor diversities were associated with survival. Although human leukocyte antigen (HLA) A, HLA-B, and HLA-C expression was not prognostic, the HLA-B*07:02 allele was associated with the best overall response. In contrast, overexpression of immune exhaustion-related genes and cytotoxic T-cell and natural killer cell exhaustion phenotypes were associated with ICB resistance and poorer prognosis. CONCLUSIONS: Integrated exome/transcriptome profiling with MSI quantification identified MSI burden and adaptive immune repertoire diversity as potential correlates of response and survival following ICB. These findings suggest a mechanistic link among genomic instability, antigen recognition diversity, and immunotherapy benefit.
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