Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer

Bhavana Palakurthi, Shaneann R. Fross, Ian H. Guldner, Emilija Aleksandrovic, Xiyu Liu, Anna K. Martino, Qingfei Wang, Ryan A. Neff, Samantha M. Golomb, Cheryl Lewis, Yan Peng, Erin N. Howe and Siyuan Zhang ()
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Bhavana Palakurthi: College of Science, University of Notre Dame
Shaneann R. Fross: College of Science, University of Notre Dame
Ian H. Guldner: College of Science, University of Notre Dame
Emilija Aleksandrovic: College of Science, University of Notre Dame
Xiyu Liu: College of Science, University of Notre Dame
Anna K. Martino: College of Science, University of Notre Dame
Qingfei Wang: College of Science, University of Notre Dame
Ryan A. Neff: College of Science, University of Notre Dame
Samantha M. Golomb: College of Science, University of Notre Dame
Cheryl Lewis: University of Texas Southwestern Medical Center
Yan Peng: University of Texas Southwestern Medical Center
Erin N. Howe: College of Science, University of Notre Dame
Siyuan Zhang: College of Science, University of Notre Dame

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.

Date: 2023
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DOI: 10.1038/s41467-023-37727-y

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