Alcaraz-Sanabria Ana, Baliu-Piqué Mariona, Saiz-Ladera Cristina, Rojas Katerin, Manzano Aránzazu, Marquina Gloria, Casado Antonio, Cimas Francisco J, Pérez-Segura Pedro, Pandiella Atanasio, Gyorffy Balázs, Ocana Alberto
Translational Oncology Laboratory, Centro Regional de Investigaciones Biomedicas, Castilla-La Mancha University, Albacete, Spain.
Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, Madrid, Spain.
Front Oncol. 2020 Jan 10;9:1486. doi: 10.3389/fonc.2019.01486. eCollection 2019.
There is an unmet need for new therapies in metastatic ovarian cancer and basal-like breast cancer since no curative therapies are currently available. Immunotherapy has shown to be active in several solid tumors, but particularly more in those where a pre-activated immune state does exist. In this work, we aim to identify biomarkers that could distinguish immune-activated tumors and predict response to therapies in ovarian and basal-like breast cancer, as well as their association with the level of tumor immune infiltration. We found that the combined expression of IFNG, CD30, CXCL13, and PRF1 correlated with better overall survival (OS) in advanced stage ovarian cancer. This was confirmed using an independent dataset from TCGA. Interestingly, we observed that this gene combination also predicted for better prognosis in ovarian tumors with low mutational load, which typically respond less to immunotherapy. Expression of IFNG, CD30, CXCL13, and PRF1 was associated with increased level of immune infiltrates (CD8 T cells, dendritic cells, and neutrophils) within the tumor. Moreover, we found that these gene signature also correlated with an increased OS and with a higher level of tumor immune infiltrates (B cells, CD8 T cells, CD4 T cells, neutrophils, and dendritic cells) in basal-like breast cancer. In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.
由于目前尚无治愈转移性卵巢癌和基底样乳腺癌的疗法，因此对新疗法存在未满足的需求。免疫疗法已在多种实体瘤中显示出活性，但在那些确实存在预激活免疫状态的实体瘤中活性尤其更高。在这项研究中，我们旨在鉴定能够区分免疫激活肿瘤并预测卵巢癌和基底样乳腺癌对疗法反应的生物标志物，以及它们与肿瘤免疫浸润水平的关联。我们发现，IFNG、CD30、CXCL13和PRF1的联合表达与晚期卵巢癌更好的总生存期（OS）相关。这在使用来自TCGA的独立数据集时得到了证实。有趣的是，我们观察到这种基因组合在低突变负荷的卵巢肿瘤中也预示着更好的预后，而低突变负荷的卵巢肿瘤通常对免疫疗法反应较小。IFNG、CD30、CXCL13和PRF1的表达与肿瘤内免疫浸润（CD8 T细胞、树突状细胞和中性粒细胞）水平的增加相关。此外，我们发现这些基因特征也与基底样乳腺癌中OS的增加以及更高水平的肿瘤免疫浸润（B细胞、CD8 T细胞、CD4 T细胞、中性粒细胞和树突状细胞）相关。总之，我们的分析鉴定出了具有识别免疫激活的卵巢癌和基底样乳腺癌的潜力的基因特征，这些癌症预后良好，并且在低突变负担的肿瘤中具有显著的预测能力。所呈现的结果引发了一个假设的形成，但需要前瞻性临床研究来支持潜在的临床应用。
