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
  • 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. [email protected].
  • 5. Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA. [email protected].
  • 6. Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA. [email protected].
  • 7. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA. [email protected].
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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