Iglesia Michael D, Parker Joel S, Hoadley Katherine A, Serody Jonathan S, Perou Charles M, Vincent Benjamin G
Affiliations of authors: Lineberger Comprehensive Cancer Center (MDI, JSP, KAH, JSS, CMP, BGV), Curriculum in Genetics and Molecular Biology (MDI, JSP), Department of Medicine (JSS, BGV), Department of Genetics (KAH, CMP), Department of Microbiology and Immunology (JSS), and Department of Pathology & Laboratory Medicine (CMP), University of North Carolina, Chapel Hill, Chapel Hill, NC.
J Natl Cancer Inst. 2016 Jun 22;108(11). doi: 10.1093/jnci/djw144. Print 2016 Nov.
Immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors. The precise makeup and prognostic relevance of immune infiltrates across a broad spectrum of tumors remain unclear.
Using mRNA sequencing data from The Cancer Genome Atlas (TCGA) from 11 tumor types representing 3485 tumors, we evaluated lymphocyte and macrophage gene expression by tissue type and by genomic subtypes defined within and across tumor tissue of origin (Cox proportional hazards, Pearson correlation). We investigated clonal diversity of B-cell infiltrates through calculating B-cell receptor (BCR) repertoire sequence diversity. All statistical tests were two-sided.
High expression of T-cell and B-cell signatures predicted improved overall survival across many tumor types including breast, lung, and melanoma (breast CD8_T_Cells hazard ratio [HR] = 0.36, 95% confidence interval [CI] = 0.16 to 0.81, P = .01; lung adenocarcinoma B_Cell_60gene HR = 0.71, 95% CI = 0.58 to 0.87, P = 7.80E-04; melanoma LCK HR = 0.86, 95% CI = 0.79 to 0.94, P = 6.75E-04). Macrophage signatures predicted worse survival in GBM, as did B-cell signatures in renal tumors (Glioblastoma Multiforme [GBM]: macrophages HR = 1.62, 95% CI = 1.17 to 2.26, P = .004; renal: B_Cell_60gene HR = 1.17, 95% CI = 1.04 to 1.32, P = .009). BCR diversity was associated with survival beyond gene segment expression in melanoma (HR = 2.67, 95% CI = 1.32 to 5.40, P = .02) and renal cell carcinoma (HR = 0.36, 95% CI = 0.15 to 0.87, P = .006).
These data support existing studies suggesting that in diverse tissue types, heterogeneous immune infiltrates are present and typically portend an improved prognosis. In some tumor types, BCR diversity was also associated with survival. Quantitative genomic signatures of immune cells warrant further testing as prognostic markers and potential biomarkers of response to cancer immunotherapy.
肿瘤微环境中的免疫浸润与部分实体瘤患者生存率的提高有关。广泛肿瘤类型中免疫浸润的精确组成及预后相关性仍不明确。
利用来自癌症基因组图谱（TCGA）的11种肿瘤类型（共3485个肿瘤）的mRNA测序数据，我们按组织类型以及按肿瘤起源组织内和跨肿瘤起源组织定义的基因组亚型评估淋巴细胞和巨噬细胞基因表达（Cox比例风险模型、Pearson相关性）。我们通过计算B细胞受体（BCR）库序列多样性来研究B细胞浸润的克隆多样性。所有统计检验均为双侧检验。
T细胞和B细胞特征的高表达预示着包括乳腺癌、肺癌和黑色素瘤在内的多种肿瘤类型患者的总生存率提高（乳腺癌CD8_T细胞风险比[HR]=0.36，95%置信区间[CI]=0.16至0.81，P = 0.01；肺腺癌B_Cell_60基因HR = 0.71，95% CI = 0.58至0.87，P = 7.8×10⁻⁴；黑色素瘤LCK HR = 0.86，95% CI = 0.79至0.94，P = 6.75×10⁻⁴）。巨噬细胞特征预示着胶质母细胞瘤患者的生存率更差，肾肿瘤中的B细胞特征也是如此（多形性胶质母细胞瘤[GBM]：巨噬细胞HR = 1.62，95% CI = 1.17至2.26，P = 0.004；肾：B_Cell_60基因HR = 1.17，95% CI = 1.04至1.32，P = 0.009）。在黑色素瘤（HR = 2.67，95% CI = 1.32至5.40，P = 0.02）和肾细胞癌（HR = 0.36，95% CI = 0.15至0.87，P = 0.006）中，BCR多样性与基因片段表达以外的生存率相关。
这些数据支持现有研究，表明在不同组织类型中存在异质性免疫浸润，且通常预示着预后改善。在某些肿瘤类型中，BCR多样性也与生存率相关。免疫细胞的定量基因组特征作为预后标志物和癌症免疫治疗反应的潜在生物标志物值得进一步测试。
