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

Zoila A. Lopez-Bujanda, Michael C. Haffner, Matthew G. Chaimowitz, Nivedita Chowdhury, Nicholas J. Venturini, Radhika A. Patel, Aleksandar Obradovic, Corey S. Hansen, Joanna Jacków, Janielle P. Maynard, Karen S. Sfanos, Cory Abate-Shen, Charles J. Bieberich, Paula J. Hurley, Mark J. Selby, Alan J. Korman, Angela M. Christiano, Angelo M. De Marzo, Charles G. Drake*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)803-818
Number of pages16
JournalNature Cancer
Volume2
Issue number8
Early online date19 Jul 2021
DOIs
Publication statusPublished - Aug 2021

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