Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419.
Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419.
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DOI：
10.3389/fonc.2022.818693
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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作者：
三阴性乳腺癌（TNBC）是乳腺癌的侵袭性变体，其缺乏雌激素和孕激素受体（ER和PR）和HER 2的表达。近50%的晚期TNBC患者会发生脑转移（BrM），通常伴有进行性颅外疾病。免疫疗法在晚期TNBC的治疗中显示出前景;然而，BrM的免疫结构在很大程度上仍然未知。我们对TNBC BrM和匹配的原发性肿瘤进行了全面分析，以表征TNBC BrM的基因组和免疫景观，从而为这种侵袭性疾病的免疫治疗策略的发展提供信息。对来自UNC-Chapel Hill的LCCC 1419生物库的临床TNBC患者的BrM和原发性肿瘤的福尔马林固定的石蜡包埋样品（n = 25，n = 9对匹配对）进行全外显子组测序（WES）和RNA测序。通过DNA测序分析匹配的血液，作为肿瘤WES的比较，以鉴定体细胞变体。进行了全面的基因组学评估，包括突变和拷贝数改变分析、新抗原预测和肿瘤免疫微环境的转录组学分析。原发性和BrM组织通过免疫组织化学确认为TNBC（23/25原发性，16/17 BrM），并且通过PAM 50确认为基底内在亚型（13/15原发性和16/19 BrM）。与原发性肿瘤相比，BrM表现出更高的肿瘤突变负荷。TP 53是最常见的突变基因，在50%的样本中发生了改变。新抗原预测显示，升高的癌睾丸抗原和内源性逆转录病毒衍生的MHC I类结合肽在原发性肿瘤和BrM和预测，单核苷酸变异（SNV）衍生的肽显着较高的BrM。BrM表现出降低的免疫基因签名表达，尽管与成纤维细胞相关的伤口愈合相关的签名在BrM中升高。BrM中T和B细胞受体多样性的增加也减少。相对于原发性TNBC，BrM具有更高的突变负荷和SNV衍生的新抗原表达沿着降低的免疫基因标签表达。与改善的存活相关的免疫特征，包括T细胞特征。进一步的研究将把这些发现扩展到同一生物库中的其他乳腺癌亚型。需要探索免疫调节方法，包括疫苗应用和免疫检查点抑制，以增强TNBC BrM的抗肿瘤免疫力。
Triple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease. Whole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed. Primary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM. BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
8.8
作者：
Jayasinghe RG;Cao S;Gao Q;Wendl MC;Vo NS;Reynolds SM;Zhao Y;Climente-González H;Chai S;Wang F;Varghese R;Huang M;Liang WW;Wyczalkowski MA;Sengupta S;Li Z;Payne SH;Fenyö D;Miner JH;Walter MJ;Cancer Genome Atlas Research Network;Vincent B;Eyras E;Chen K;Shmulevich I;Chen F;Ding L
通讯作者：
Ding L
影响因子：
5.2
作者：
Gelsi-Boyer, W;Orsetti, B;Chaffanet, M
通讯作者：
Chaffanet, M
ENSA的拷贝数扩增可通过胆固醇生物合成促进三阴性乳腺癌的进展。
影响因子：
16.6
作者：
Chen YY;Ge JY;Zhu SY;Shao ZM;Yu KD
通讯作者：
Yu KD
影响因子：
9.8
作者：
Chang HY;Sneddon JB;Alizadeh AA;Sood R;West RB;Montgomery K;Chi JT;van de Rijn M;Botstein D;Brown PO
通讯作者：
Brown PO