2. Academic Validation
  3. Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer

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

  • Nat Commun. 2023 Apr 13;14(1):2109. doi: 10.1038/s41467-023-37727-y.
Bhavana Palakurthi 1 2,  Shaneann R Fross 1 2,  Ian H Guldner 1 2,  Emilija Aleksandrovic 1 2,  Xiyu Liu 1 2,  Anna K Martino 1,  Qingfei Wang 1 2,  Ryan A Neff 1,  Samantha M Golomb 1 2,  Cheryl Lewis 3,  Yan Peng 3,  Erin N Howe 1 2,  Siyuan Zhang 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA.
  • 2 Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA.
  • 3 Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
  • 4 Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA. Siyuan.Zhang@UTSouthwestern.edu.
  • 5 Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA. Siyuan.Zhang@UTSouthwestern.edu.
  • 6 Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA. Siyuan.Zhang@UTSouthwestern.edu.
  • 7 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA. Siyuan.Zhang@UTSouthwestern.edu.
PMID: 37055410 DOI: 10.1038/s41467-023-37727-y
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.

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