2. Academic Validation
  3. Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression

Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression

  • Nat Cancer. 2021 Aug;2(8):803-818. doi: 10.1038/s43018-021-00227-3.
Zoila A Lopez-Bujanda 1 2 3,  Michael C Haffner 1 4,  Matthew G Chaimowitz 2,  Nivedita Chowdhury 1 2,  Nicholas J Venturini 2,  Radhika A Patel 4,  Aleksandar Obradovic 2,  Corey S Hansen 5,  Joanna Jacków 5 6,  Janielle P Maynard 1,  Karen S Sfanos 1 7 8,  Cory Abate-Shen 9 10 11 12,  Charles J Bieberich 13 14,  Paula J Hurley 7 15,  Mark J Selby 16 17,  Alan J Korman 16 18,  Angela M Christiano 5 19,  Angelo M De Marzo 1 7 8,  Charles G Drake 20 21 22
Affiliations

Affiliations

  • 1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • 3 Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine, Skirball Institute, New York University School of Medicine, New York, NY, USA.
  • 4 Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
  • 5 Department of Dermatology, Columbia University, New York, NY, USA.
  • 6 St John's Institute of Dermatology, King's College London, London, England.
  • 7 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 9 Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA.
  • 10 Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 11 Department of Urology, Columbia University Irving Medical Center, New York, NY, USA.
  • 12 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
  • 13 Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD, USA.
  • 14 University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
  • 15 Department of Hematology/Oncology, Vanderbilt University, Nashville, TN, USA.
  • 16 Bristol-Myers Squibb, Redwood City, CA, USA.
  • 17 Walking Fish Therapeutics, San Francisco, CA, USA.
  • 18 Vir Biotechnology, San Francisco, CA, USA.
  • 19 Department of Genetics and Development, Columbia University, New York, NY, USA.
  • 20 Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
  • 21 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. [email protected].
  • 22 Division of Hematology/Oncology, Department of Medicine, Columbia University, New York, NY, USA. [email protected].
PMID: 35122025 DOI: 10.1038/s43018-021-00227-3
Abstract

Unlike several other tumor types, prostate Cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate Cancer progression and resistance to ICB, we analyzed prostate Cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog CXCL15 in prostate epithelial cells. We showed that these chemokines drove subsequent intratumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration, and highlight blockade of the IL-8/CXCR2 axis as a potential therapeutic intervention.

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