Brockwell Natasha K, Rautela Jai, Owen Katie L, Gearing Linden J, Deb Siddhartha, Harvey Kate, Spurling Alex, Zanker Damien, Chan Chia-Ling, Cumming Helen E, Deng Niantao, Zakhour Jasmine M, Duivenvoorden Hendrika M, Robinson Tina, Harris Marion, White Michelle, Fox Jane, Ooi Corinne, Kumar Beena, Thomson Jacqui, Potasz Nicole, Swarbrick Alex, Hertzog Paul J, Molloy Tim J, Toole Sandra O', Ganju Vinod, Parker Belinda S
1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC Australia.
2Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
NPJ Precis Oncol. 2019 Aug 29;3:21. doi: 10.1038/s41698-019-0093-2. eCollection 2019.
Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting long-term survival post-chemotherapy in patients with TNBC is difficult, yet enhanced infiltration of tumor infiltrating lymphocytes (TILs) has been associated with therapeutic response and reduced risk of metastatic relapse. Immune biomarkers that predict the immune state of a tumor and risk of metastatic relapse pre- or mid-neoadjuvant chemotherapy are urgently needed to allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. Utilizing a neoadjuvant chemotherapy trial where TNBC patients had sequential biopsies taken, we demonstrate that measurement of T-cell subsets and effector function, specifically CD45RO expression, throughout chemotherapy predicts risk of metastatic relapse. Furthermore, we identified the tumor inherent interferon regulatory factor IRF9 as a marker of active intratumoral type I and II interferon (IFN) signaling and reduced risk of distant relapse. Functional implications of tumor intrinsic IFN signaling were demonstrated using an immunocompetent mouse model of TNBC, where enhanced type I IFN signaling increased anti-tumor immunity and metastasis-free survival post-chemotherapy. Using two independent adjuvant cohorts we were able to validate loss of IRF9 as a poor prognostic biomarker pre-chemotherapy. Thus, IRF9 expression may offer early insight into TNBC patient prognosis and tumor heat, allowing for identification of patients that are unlikely to respond to chemotherapy alone and could benefit from further immune-based therapeutic intervention.
与其他亚型相比，被诊断为三阴性乳腺癌（TNBC）的患者发生快速转移的风险增加。预测TNBC患者化疗后的长期生存情况很困难，然而肿瘤浸润淋巴细胞（TILs）浸润增加与治疗反应及转移复发风险降低相关。迫切需要能在新辅助化疗前或化疗中期预测肿瘤免疫状态及转移复发风险的免疫生物标志物，以便能更早实施可能降低TNBC患者死亡率的替代疗法。利用一项新辅助化疗试验，该试验中TNBC患者接受了序贯活检，我们证明在整个化疗过程中测量T细胞亚群和效应功能，特别是CD45RO表达，可预测转移复发风险。此外，我们确定肿瘤内在的干扰素调节因子IRF9是肿瘤内I型和II型干扰素（IFN）信号激活及远处复发风险降低的标志物。使用TNBC的免疫活性小鼠模型证明了肿瘤内在IFN信号的功能意义，其中增强的I型IFN信号增加了化疗后的抗肿瘤免疫力和无转移生存期。通过两个独立的辅助队列，我们能够验证化疗前IRF9缺失作为不良预后生物标志物的情况。因此，IRF9表达可能为TNBC患者的预后和肿瘤状态提供早期洞察，从而识别出不太可能仅对化疗有反应且可能从进一步基于免疫的治疗干预中获益的患者。
