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某些三阴性乳腺癌（TNBC）免疫细胞浸润性较高，而其他较低，原因尚不明确。淋巴细胞浸润性较高、预后良好的TNBC，与免疫浸润较少、预后较差的TNBC，其基因组差异亦不明确。因此，了解免疫监视如何影响癌症基因组，可以帮助选择患者并开发更有效的免疫治疗策略。 2017年7月27日，《美国医学会杂志肿瘤学分册》在线发表德国法兰克福歌德大学、美国耶鲁大学医学院癌症中心、德国吕贝克大学医院、意大利圣拉斐尔大学医院的研究报告，对TNBC免疫浸润程度与基因组指标的相关性进行了探讨，结果发现，免疫基因高表达的TNBC克隆异质性较低、拷贝数变化较少、体细胞突变性较低、新抗原负荷较低。因此，高免疫性TNBC的抗肿瘤免疫监视可能导致克隆清除、克隆异质性降低、基因组简化；存活肿瘤细胞群与免疫监视接近平衡，可解释预后较好、免疫不良TNBC的基因组多样性较强，免疫抑制作用较弱。 该研究于2015年6月1日～2017年1月31日使用癌症基因组图谱（TCGA）乳腺癌数据集（1215例）的DNA和RNA测序数据和信使RNA表达结果，计算既往描述的免疫元基因表达值和组织学淋巴细胞计数，量化免疫浸润，并将TNBC预后进行分类。使用国际乳腺癌分子分类联盟（METABRIC）数据集作为独立验证队列，比较高免疫性预后良好TNBC队列与低免疫性预后不良TNBC队列的克隆异质性、体细胞总突变负荷、新抗原负荷、体细胞拷贝数变化水平，还比较了119个典型癌基因突变的分布情况。主要结局衡量指标为免疫预后类别与癌症基因组指标之间的相关性。 结果发现，根据193例TNBC标本及其患者生存信息：
通过相同TCGA数据集和独立METABRIC数据集的各种免疫元基因，证实该研究结果的可靠性。 因此，本研究表明高免疫性TNBC可能在免疫监视下不断消除许多产生免疫性的克隆，导致克隆异质性较低。这些TNBC亚组也可能从免疫检查点抑制剂疗法获益，使平衡倾向有利于免疫系统。 JAMA Oncol. 2017 Jul 27. [Epub ahead of print] Association Between Genomic Metrics and Immune Infiltration in Triple-Negative Breast Cancer. Thomas Karn; Tingting Jiang; Christos Hatzis; Nicole Sanger; Ahmed El-Balat; Achim Rody; Uwe Holtrich; Sven Becker; Giampaolo Bianchini; Lajos Pusztai. Goethe-University Frankfurt, Frankfurt, Germany; Yale School of Medicine, New Haven, Connecticut; University Hospital Lübeck, Lübeck, Germany; Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy. This study examines the association between genomic metrics and the extent of immune infiltration in triple-negative breast cancers. QUESTION: What are the genomic differences between triple-negative breast cancers with high lymphocytic infiltration and good prognosis and triple-negative breast cancers with less immune infiltration and worse prognosis? FINDINGS: In this study of genomic data sets, triple-negative breast cancers with high immune gene expression had lower clonal heterogeneity, fewer copy number alterations, lower somatic mutation, and lower neoantigen loads. MEANING: This study suggests that antitumor immune surveillance in immune-rich triple-negative breast cancers may lead to elimination of clones, lower clonal heterogeneity, and “simpler” genomes; the surviving neoplastic cell population exists at a near equilibrium with immune surveillance, explaining the better prognosis, and immune-poor triple-negative breast cancers have greater genomic diversity attributable to lesser immune restraint. IMPORTANCE: Why some triple-negative breast cancers (TNBCs) have high and others have low immune cell infiltration is unknown. Understanding how immune surveillance shapes the cancer genome could help in the selection of patients and the development of more effective immunotherapy strategies. OBJECTIVE: To examine the association between genomic metrics and the extent of immune infiltration in TNBCs. DESIGN, SETTING, AND PARTICIPANTS: This study, performed from June 1, 2015, through January 31, 2017, used DNA and RNA sequencing data and messenger RNA expression results from The Cancer Genome Atlas (TCGA) breast cancer data set (n=1215) to calculate previously described immune metagene expression values and histologic lymphocyte counts to quantify immune infiltration and assign prognostic categories to TNBCs. It used the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set as an independent validation cohort. The study compared clonal heterogeneity, somatic total mutational load, neoantigen load, and somatic copy number alteration levels between immune-rich TNBC cohorts with good prognosis and immune-poor TNBC cohorts with poor prognosis. The study also compared the distribution of mutations in 119 canonical cancer genes. MAIN OUTCOMES AND MEASURES: Correlation between immune prognostic category and genomic metrics of the cancer. RESULTS: This study of 193 TNBC samples with patient survival information found an inverse association between clonal heterogeneity and immune metagene expression (ρ=-0.395, P=2×10-8). The study also found an inverse association between immune metagene expression and somatic copy number alteration levels (ρ=-0.484, P=2×10-10). Lymphocyte-rich TNBCs with good prognosis had significantly lower mutation and neoantigen counts than did lymphocyte-poor TNBCs with poor prognosis. The robustness of the study results was confirmed by using various immune metagenes in the same TCGA data set and in the independent METABRIC data set. CONCLUSIONS AND RELEVANCE: This study suggests that immune-rich TNBCs may be under an immune surveillance that continuously eliminates many immunogenic clones, resulting in lower clonal heterogeneity. These cancers may also represent the subset of TNBCs that could derive benefit from immune checkpoint inhibitor therapy to tilt the balance in favor of the immune system. DOI: 10.1001/jamaoncol.2017.2140 |
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