Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC (#107)

Natasha K Brockwell 1 , Jai Rautela 2 , Linden J Gearing 3 , Alex Swarbrick 4 , Tim Molloy 5 , Sandra O'Toole 4 , Vinod Ganju 3 , Belinda S Parker 1
  1. La Trobe University, Bundoora, VIC, Australia
  2. Walter and Eliza Hall institute , Melbourne, VIC, Australia
  3. Clinical Translational Research , Hudson Institute for Medical Research, Melbourne , Victoria, Australia
  4. Garvan Institute of Medical Research , Sydney , NSW, Australia
  5. St Vincents Centre for Applied Medical Research , Darlinghurst , Sydney , Australia

Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting chemotherapeutic benefit 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. The use of specific immune biomarkers that predict chemoresistance pre-treatment or during neoadjuvant therapy could allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. We characterized the T cell microenvironment and tumor inherent IFNs by multiplex and conventional IHC in a neoadjuvant TNBC sequential biopsy chemotherapy trial. Transcriptional analysis was used assess whether a single transcriptional factor (IRF9) could reflect active IFN signaling pathways. Two independent cohorts were used to validate IRF9 as prognostic. A mouse model of TNBC was used to evaluate the direct impact of tumor inherent type I IFN signaling on the T cell landscape, disease progression and chemotherapeutic sensitivity. Measurement of T cell subsets and their effector function throughout chemotherapy predicts risk of metastatic relapse. Furthermore, tumor inherent IRF9 is a marker of active intratumoral type I and II interferon (IFN) signaling, which is associated with an enhanced tissue resident memory T cell signature and reduced risk of distant relapse. Enhanced type I IFN signaling increased anti-tumor immunity, chemotherapeutic response and metastasis free survival in vivo. IRF9 was confirmed as a biomarker of long term survival in TNBC. 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. These findings have initiated the study of tumor immune reactivity in other cancers in order to help predict response to immunotherapy.