Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer
Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer
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DOI：
10.1158/1078-0432.ccr-18-0468
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发表时间：
2019-07-15
影响因子：
11.5
通讯作者：
Nathanson, Katherine L.
中科院分区：
文献类型：
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作者：
Kraya, Adam A.;Maxwell, Kara N.;Nathanson, Katherine L.
目的：BRCA1/2基因突变的乳腺癌有相对较高的突变负荷，提示免疫检查点阻断可能是一种潜在的治疗选择。然而，免疫细胞的渗透程度差异很大，导致这种差异的分子特征尚不清楚。实验设计：我们假设基因组特征可能预测BRCA1/2乳腺癌的免疫原性。使用癌症基因组图谱(TCGA)的基因组数据，我们比较了有(89)和没有(770)生殖系或体细胞BRCA1/2改变的乳腺癌。我们还利用WES和IHC研究了来自宾夕法尼亚大学的35例具有种系BRCA1/2突变的乳腺癌。结果：我们发现，在BRCA1/2突变的乳腺癌中，同源重组缺陷评分与基于表达的免疫指标[细胞溶解指数(P=0.04)、免疫估计(P=0.002)、II型IFN信号转导(P=0.002)]呈负相关，尽管与突变/新抗原负荷有关。此外，不存在种系和体细胞BRCA1/2突变的等位基因特异性杂合性丢失(LOH阴性；P=0.003)或亚克隆性(P=0.003)，可预测较高的细胞溶解活性。基因集分析发现，多种先天和获得性免疫途径汇聚在核因子-kB上，可能有助于这种高免疫原性。PEN乳腺癌组织中CD8(+)(P=0.039)和CD8(+)浸润物(P=0.037)和PDL1表达增加(P=0.012)。与激素受体高表达的乳腺癌相比，低激素受体表达的三阴性乳腺癌的CD8(+)T细胞(P=0.0011)和穿孔素1的表达(P=0.014)要高得多。结论：激素受体评分和激素受体亚型可以预测BRCA1/2乳腺癌的免疫原性，可能为设计最佳的免疫治疗策略提供参考。
Purpose: Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown.Experimental Design: We hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic BRCA1/2 alterations. We also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using WES and IHC.Results: We found that homologous recombination deficiency (HRD) scoreswere negatively associatedwith expressionbased immune indices [cytolytic index (P = 0.04), immune ESTIMATE (P = 0.002), type II IFNsignaling (P = 0.002)] despite being associated with a highermutational/neoantigen burden, in BRCA1/2 mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; P = 0.01) or subclonality (P = 0.003) of germline and somatic BRCA1/2 mutations, respectively, predicted for heightened cytolytic activity. Gene set analysis found that multiple innate and adaptive immune pathways that converge on NF-kB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD8(+) (P = 0.039) and CD8(+) infiltrates (P = 0.037) and increased PDL1 expression (P = 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8(+) T cells (P = 0.0011) and Perforin 1 expression (P = 0.014) compared with hormone receptor-positive HRD-high cancers.Conclusions: HRD scores and hormone receptor subtype are predictive of immunogenicity in BRCA1/2 breast cancers and may inform the design of optimal immune therapeutic strategies.