Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics

Hamad Alshetaiwi1,2, Nicholas Pervolarakis3, Laura Lynn McIntyre4, Dennis Ma1, Quy Nguyen1, Jan Akara Rath5, Kevin Nee1, Grace Hernandez6, Katrina Evans6, Leona Torosian1, Anushka Silva1, Craig Walsh4, Kai Kessenbrock7

  1. Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  2. Department of Pathology, University of Hail, Hail 2440, Saudi Arabia.
  3. Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
  4. Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
  5. Ludwig Institute for Cancer Research, University of Lausanne, Epalinges 1066, Switzerland.
  6. Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
  7. Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. kai.kessenbrock@uci.edu.

Abstract

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.

Presented By Hamad Alshetaiwi

Cancer BiologyNicholas Liao2020-02 (Feb)