S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models
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 clinic...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
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| Series: | Communications Medicine |
| Online Access: | https://doi.org/10.1038/s43856-024-00444-8 |
| _version_ | 1797273484361990144 |
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| author | Lauren R. Begg Adrienne M. Orriols Markella Zannikou Chen Yeh Pranathi Vadlamani Deepak Kanojia Rosemary Bolin Sara F. Dunne Sanjeev Balakrishnan Roman Camarda Diane Roth Nicolette A. Zielinski-Mozny Christina Yau Athanassios Vassilopoulos Tzu-Hsuan Huang Kwang-Youn A. Kim Dai Horiuchi |
| author_facet | Lauren R. Begg Adrienne M. Orriols Markella Zannikou Chen Yeh Pranathi Vadlamani Deepak Kanojia Rosemary Bolin Sara F. Dunne Sanjeev Balakrishnan Roman Camarda Diane Roth Nicolette A. Zielinski-Mozny Christina Yau Athanassios Vassilopoulos Tzu-Hsuan Huang Kwang-Youn A. Kim Dai Horiuchi |
| author_sort | Lauren R. Begg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:45:02Z |
| format | Article |
| id | doaj.art-bbe12d3b38a147d5bf67e56921985ad3 |
| institution | Directory Open Access Journal |
| issn | 2730-664X |
| language | English |
| last_indexed | 2024-03-07T14:45:02Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Medicine |
| spelling | doaj.art-bbe12d3b38a147d5bf67e56921985ad32024-03-05T20:05:26ZengNature PortfolioCommunications Medicine2730-664X2024-02-014111710.1038/s43856-024-00444-8S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse modelsLauren R. Begg0Adrienne M. Orriols1Markella Zannikou2Chen Yeh3Pranathi Vadlamani4Deepak Kanojia5Rosemary Bolin6Sara F. Dunne7Sanjeev Balakrishnan8Roman Camarda9Diane Roth10Nicolette A. Zielinski-Mozny11Christina Yau12Athanassios Vassilopoulos13Tzu-Hsuan Huang14Kwang-Youn A. Kim15Dai Horiuchi16Northwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineCenter for Comparative Medicine, Northwestern UniversityHigh Throughput Analysis Laboratory, Northwestern UniversityUniversity of California, San FranciscoUniversity of California, San FranciscoNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineUniversity of California, San FranciscoNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineNorthwestern University Feinberg School of MedicineAbstract 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.https://doi.org/10.1038/s43856-024-00444-8 |
| spellingShingle | Lauren R. Begg Adrienne M. Orriols Markella Zannikou Chen Yeh Pranathi Vadlamani Deepak Kanojia Rosemary Bolin Sara F. Dunne Sanjeev Balakrishnan Roman Camarda Diane Roth Nicolette A. Zielinski-Mozny Christina Yau Athanassios Vassilopoulos Tzu-Hsuan Huang Kwang-Youn A. Kim Dai Horiuchi S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models Communications Medicine |
| title | S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models |
| title_full | S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models |
| title_fullStr | S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models |
| title_full_unstemmed | S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models |
| title_short | S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models |
| title_sort | s100a8 a9 predicts response to pim kinase and pd 1 pd l1 inhibition in triple negative breast cancer mouse models |
| url | https://doi.org/10.1038/s43856-024-00444-8 |
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