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NPJ Precis Oncol. 2019 Aug 29;3:21. doi: 10.1038/s41698-019-0093-2. eCollection 2019.

Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC.

Author information

1
1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC Australia.
2
2Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
3
3Cancer Immunology and Therapeutics Programs, Peter MacCallum Cancer Centre, Melbourne, Australia.
4
4The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC Australia.
5
5Department of Medical Biology, University of Melbourne, Melbourne, VIC Australia.
6
6Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC Australia.
7
7Department of Molecular and Translational Science, Monash University, Clayton, VIC Australia.
8
Anatpath, Gardenvale, VIC Australia.
9
Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Sydney, NSW Australia.
10
10Monash Health, Clayton, VIC Australia.
11
11Monash Health School of Clinical Sciences, Monash University, Clayton, VIC Australia.
12
Penninsula Health, Frankston, VIC Australia.
13
13St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW Australia.
14
14St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW Australia.
15
15Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW Australia.
16
16Sydney Medical School, University of Sydney, Sydney, NSW Australia.
17
Australian Clinical Labs, Bella Vista, NSW Australia.

Abstract

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.

KEYWORDS:

Breast cancer; Prognostic markers; Tumour biomarkers

Conflict of interest statement

Competing interestS.O.T. has received honoraria for serving on advisory boards for AstraZeneca, BMS, and Merck. B.S.P. receives collaborative funding for another project from AstraZeneca/MedImmune. B.S.P. is sole inventor on patent application PCT/AU2016/050392 that covers the method of diagnosis of breast cancer (IRF9). Remaining authors declare no competing interests.

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