TY - JOUR
T1 - Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression
AU - Lopez-Bujanda, Zoila A.
AU - Haffner, Michael C.
AU - Chaimowitz, Matthew G.
AU - Chowdhury, Nivedita
AU - Venturini, Nicholas J.
AU - Patel, Radhika A.
AU - Obradovic, Aleksandar
AU - Hansen, Corey S.
AU - Jacków, Joanna
AU - Maynard, Janielle P.
AU - Sfanos, Karen S.
AU - Abate-Shen, Cory
AU - Bieberich, Charles J.
AU - Hurley, Paula J.
AU - Selby, Mark J.
AU - Korman, Alan J.
AU - Christiano, Angela M.
AU - De Marzo, Angelo M.
AU - Drake, Charles G.
N1 - Funding Information:
We thank members of the Drake laboratory for discussion and insightful comments; F. Veglia for advice with the in vitro suppression assays; K. C. Smith, A. Floratos and the Center for Computational Biology and Bioinformatics at Columbia University for the ChIP-seq analysis; S. Coley, T. Swayne, E. Munteanu and the Confocal and Specialized Microscopy Shared Resource at Columbia University for help with microscopy; L. Dasko-Vincent from the Sidney Kimmel Comprehensive Cancer Center Imaging Facility at Johns Hopkins University for support with the LCM; J. Pevsner for assistance with the protein homology analyses; and B. Johnson for help with the statistical analyses. This study was supported by the US Department of Defense (W81XWH-13-1-0369), US National Institutes of Health National Cancer Institute (R01: CA127153 and R01: CA183929-05), Patrick C. Walsh Fund, OneInSix Foundation and Prostate Cancer Foundation. Research reported in this publication was performed at the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under award S10OD020056. Hematoxylin and eosin/IHC staining and image collection for this work was performed at the Molecular Pathology Shared Resource and Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, supported by NIH grant P30 CA013696 (National Cancer Institute). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85111079612&partnerID=8YFLogxK
U2 - 10.1038/s43018-021-00227-3
DO - 10.1038/s43018-021-00227-3
M3 - Article
AN - SCOPUS:85111079612
SN - 2662-1347
VL - 2
SP - 803
EP - 818
JO - Nature Cancer
JF - Nature Cancer
IS - 8
ER -
