三阴性乳腺癌“冷肿瘤”治疗新契机
三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗无效，治疗方法有限，预后较差，尤其非免疫炎症型肿瘤，被认为是“免疫冷淡型肿瘤”，对免疫治疗效果也不佳。人类白细胞抗原HLA-I不仅参与抗肿瘤免疫反应和肿瘤微环境表现型，而且还是免疫治疗结局不良的预测因子。不过，HLA功能状态对于三阴性乳腺癌的重要性仍不明确。
2021年10月6日，《英国医学杂志》旗下《癌症免疫治疗杂志》在线发表复旦大学附属肿瘤医院周逸凡、肖毅、金希、狄根红、江一舟、邵志敏等学者的研究报告，通过综合分析，揭示了HLA-I杂合性缺失对三阴性乳腺癌的预后价值。
该研究利用全球最大的三阴性乳腺癌原始多组学数据集，从HLA-I同源性缺失和杂合性缺失的角度，对三阴性乳腺癌的HLA-I状态进行系统分析，对HLA-I状态的预后意义进行定量分析。为了解释HLA-I状态预后价值的潜在机制，还对其突变特征、拷贝数改变、新生抗原和肿瘤内异质性进行测定。此外，还对HLA-I功能状态与肿瘤免疫微环境的相关性进行分析。
结果发现，三阴性乳腺癌的HLA-I杂合性缺失率和同源性缺失率分别为18%和21%。HLA-I杂合性缺失与HLA-I同源性缺失相比，可独立预测三阴性乳腺癌患者的无复发生存。尤其对于非免疫炎症型肿瘤患者，HLA-I杂合性缺失与未缺失相比，无复发生存率显著较低。
此外，基因组和转录组综合分析表明，HLA-I杂合性缺失伴随着突变特征3和同源重组缺陷评分上调，这意味着DNA双链断裂修复失败。而且，HLA-I杂合性缺失与未缺失相比，突变负荷和新生抗原负荷显著较高、亚克隆显著较多。这些结果表明，虽然HLA-I杂合性缺失且DNA双链断裂修复失败肿瘤容易产生新生抗原，但是其抗原呈递能力有限，最终引起免疫选择压力变差。
因此，该研究结果揭示了HLA-I功能状态的基因组特征，并突出了HLA-I杂合性缺失对三阴性乳腺癌的预后意义。对于三阴性乳腺癌“免疫冷淡型肿瘤”，HLA-I杂合性缺失与未缺失相比，预后显著较差，但是伴随的突变特征3和同源重组缺陷评分上调，可能提示新的治疗契机，例如PARP抑制剂或铂类。
相关链接
J Immunother Cancer. 2021 Oct 6;9(10):e003371.
Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer.
Zhou YF, Xiao Y, Jin X, Di GH, Jiang YZ, Shao ZM.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
BACKGROUND: Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood.
METHODS: Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed.
RESULTS: LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure.
CONCLUSION: Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For "cold" tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.
KEYWORDS: antigen presentation; breast neoplasms
PMID: 34615706
DOI: 10.1136/jitc-2021-003371