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，诊断为三阴性乳腺癌（TNBC）的患者快速转移的风险增加。预测 TNBC 患者化疗后的长期生存很困难，但肿瘤浸润淋巴细胞 (TIL) 浸润的增强与治疗反应和降低转移复发风险相关。迫切需要预测肿瘤免疫状态以及新辅助化疗前或中期转移复发风险的免疫生物标志物，以便更早实施替代疗法，从而降低 TNBC 患者死亡率。利用新辅助化疗试验，对 TNBC 患者进行连续活检，我们证明在整个化疗过程中测量 T 细胞亚群和效应器功能，特别是 CD45RO 表达可以预测转移性复发的风险。此外，我们还发现肿瘤固有的干扰素调节因子 IRF9 作为活性肿瘤内 I 型和 II 型干扰素 (IFN) 信号传导的标志物，可降低远处复发的风险。使用具有免疫活性的 TNBC 小鼠模型证明了肿瘤内在 IFN 信号传导的功能意义，其中增强的 I 型 IFN 信号传导增加了抗肿瘤免疫力和化疗后的无转移生存。使用两个独立的辅助队列，我们​​能够验证 IRF9 的丢失作为化疗前预后不良的生物标志物。因此，IRF9 表达可以提供对 TNBC 患者预后和肿瘤热的早期了解，从而识别出不太可能对单独化疗产生反应并可以从进一步的基于免疫的治疗干预中受益的患者。