Abstract
Background: Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies. Methods: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action. Results: Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Conclusions: Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.
Original language | English (US) |
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Article number | 22 |
Journal | Communications Medicine |
Volume | 4 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2024 |
Funding
We acknowledge the following support: the Lynn Sage Breast Cancer Foundation (A.V., D.H.), the Elsa U. Pardee Foundation (A.V., D.H.), the Northwestern Medicine Catalyst Funds (D.H.), the US National Institutes of Health (NIH; R01CA258833 to D.H.), the US Department of Defense Breast Cancer Research Program (W81XWH1810053 to D.H.), the Susan G. Komen Foundation (CCR16376693 to D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (D.H.), the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the NIH\u2019s National Center for Advancing Translational Sciences (UL1TR001422). Flow cytometry experiments were carried out at the Northwestern University Flow Cytometry Core Facility, and a part of the small molecule screening was carried out at the Northwestern High Throughput Analysis Laboratory, both of which were partly supported by a National Cancer Institute Cancer Center Support Grant (P30CA060553). The content is solely the authors\u2019 responsibility and does not necessarily represent the official views of the NIH. Some of the graphical figure panels were created with BioRender.com. We thank Drs. Clare Isacke and Ute Jungwirth for providing the D2A1-M1 and -M2 lines, Levi Barse, Dr. Erica Fleming-Trujillo, and Miriam Walter for the initial characterization of the experimental models used in this study, Dr. Kai Kessenbrock for his insights into flow cytometry-based identification of MDSCs and the potential significance of targeting PIM kinases in MDSCs, Genentech for providing GDC-0339, Dr. Andrei Goga for supporting S.B. and R.C. during the construction of the initial version of bioinformatics pipeline and D.H\u2019s transition to independence, and Dr. J. Michael Bishop and Laura Sage for their encouragement.
ASJC Scopus subject areas
- Public Health, Environmental and Occupational Health
- Internal Medicine
- Epidemiology
- Medicine (miscellaneous)
- Assessment and Diagnosis