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

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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Fig. 1: ADT regulates Cxcl15 expression in murine prostate cancer cells.
Fig. 2: Androgen receptor signaling modulates IL-8 expression in human prostate cancer cells.
Fig. 3: Cxcl15 and IL-8 are upregulated in post-castration and castration-resistant prostate cancer.
Fig. 4: Castration-mediated IL-8 upregulation promotes PMN-MDSC infiltration.
Fig. 5: The Cxcl15/CXCR2 (IL-8/CXCR2) axis regulates the migration of PMN-MDSCs, but not their ability to suppress T cell function.
Fig. 6: CXCR2 blockade improves response to ICB following ADT.
Fig. 7: The therapeutic effect of the triple combination is associated with PMN-MDSC reduction.

Data availability

Microarray data from this study have been deposited in the Gene Expression Omnibus under accession code GSE171491. Previously published microarray and ChIP-seq data that were reanalyzed here are available under accession codes GSE8466, GSE56288, GSE83860 and GSE55064. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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.

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Authors

Contributions

Z.A.L.-B., M.C.H., M.G.C., N.C., N.J.V., A.O., R.A.P. and J.P.M. performed the experiments. C.S.H., J.J., C.J.B., P.J.H., M.J.S., A.J.K. and C.A.-S. contributed essential reagents. Z.A.L.-B., M.C.H., A.M.C. and C.G.D. designed and supervised the experiments. M.C.H., K.S.S. and A.M.D.M. coordinated the study on human samples. C.G.D. supervised the study. Z.A.L.-B. and C.G.D. wrote the manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Charles G. Drake.

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Competing interests

C.G.D. has served as a consultant for Agenus, Dendreon, Janssen Oncology, Eli Lilly, Merck, AstraZeneca, MedImmune, Pierre Fabre, Genentech and Genocea Biosciences. A.M.C. is a shareholder of Aclaris Therapeutics and a consultant for Dermira and Aclaris Therapeutics. Columbia University has filed a US patent claiming the benefit of US provisional patent application number 62/809,060 (inventors C.G.D. and Z.A.L.-B.) on the use of IL-8/CXCR2 blockade of PMN-MDSC recruitment to the TME for the treatment of prostate cancer. The remaining authors declare no competing interests.

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Peer review information Nature Cancer thanks Christopher Barbieri, Vincenzo Bronte and James Gulley for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Cxcl15 Regulation Upon AR signaling Stimulation and Inflammatory Stimuli in Prostate Tumor Epithelial Cells.

a, Androgen responsive prostate tumor cells progressed from castration-sensitive (CS) to androgen responsive (pADT), and eventually developed castration-resistance (CR). CR was tumor size defined as ≥ 30% of nadir tumor volume. Top, tumor growth curve of MCRedAL tumors (n = 3 mice per group, repeated x2); bottom: treatment and harvest timeline. CTX: Castration. b, Upper: sorting strategy to isolate tumor epithelial cells from a based on their expression of mCherry and their CD45CD11bF4/80 phenotype; Lower: purity check of mCherry+ sorted cells. c, Histogram of log2 fold change comparisons (SD Log2 FC) between pADT and CS groups among all the microarray transcripts (n = 3 tumors per group). d, qRT-PCR quantification of Cxcl15 in Myc-CaP cells cultured at indicated concentrations of DHT for 8hrs and TNFα (50Units/ml) for 6hrs, cells cultured in androgen-free media for 48 hours before stimulation (n = 2 independently cultured replicates per condition, repeated x2). Expression levels normalized to mean ΔCT level in samples cultured in androgen free media without TNFα or DHT. e, qRT-PCR quantification of Cxcl15 in Myc-CaP WT cells expressing either nothing, scramble (Scr) shRNA, or an anti-AR shRNA (KD: knock-down) cultured in the presence of DHT (10 nM) for 8hrs and TNFα (50Units/ml) for 6hrs, cells cultured in androgen-free media for 24hrs before DHT stimulation (n = 2 independently cultured replicates per condition, repeated x2). Expression levels normalized to mean ΔCT level in WT samples cultured in androgen free media without TNFα or DHT. f, qRT-PCR quantification of Cxcl15 in Myc-CaP cells cultured at indicated concentrations of DHT for 8hrs and TNFα (50Units/ml) for 6hrs in the presence and absence of the AR blocker Enzalutamide (10 µM), cells cultured in androgen-free media for 48hrs before stimulation (n = 2 independently cultured replicates per condition, repeated x2). Bar plots represent means with SEM. Unpaired two-tailed (d-f) t-tests were performed, p-values ≤ 0.0001 (****); p-values ≥ 0.05 (ns).

Source data

Extended Data Fig. 2 IL-8 Regulation in Prostate Tumor Epithelial Cells.

a, Percentage input bound in ChIP-qPCR assays assessing binding of AR, pSer5 Pol II, and H3K9ac at the KLK3 (PSA) promoter (top) and upstream region (bottom) in LNCaP cells cultured at indicated concentrations of DHT for 8hrs and TNFα (50Units/ml) for 6hrs, cells cultured in androgen-free media for 72hrs before DHT stimulation (n = 2 independently cultured replicates per group). b, ChIP-Seq analysis of AR and NF-κB p65 subunit at the IL-8 (CXCL8) promoter in LNCaP cells cultured in the presence of either vehicle (DMSO), DHT (100 nM), or TNFα (1000U/ml) (n = 2 replicates per group; GSE83860). c, ChIP-Seq analysis at the IL-8 (CXCL8) promoter for AR and RNA pol II binding in LNCaP cells (top), and AR binding in VCaP cells (bottom). Both cell lines were cultured in the presence of either vehicle (DMSO) or DHT (10 nM) (GSE55064). For b, loci with significant differential binding (black bar) were identified as described in materials and methods. Blue shading marks AR binding site; while orange shading marks NF-κB p65 subunit binding site. Bar plots represent means with SEM. Unpaired one-tailed t-tests were performed, p-values ≤ 0.0001 (****); p-values ≥ 0.05 (ns).

Source data

Extended Data Fig. 3 Chemokine Regulation in Prostate Tumor Epithelial Cells.

a, ChIP-Seq enrichment of AR and NF-κB p65 subunit at the CXCL1, CXCL2, CXCL5, and CXCL12 promoters in LNCaP cells cultured in the presence of either vehicle (DMSO), AR signaling (DHT: 100 nM), or an inflammatory stimuli (TNFα: 1000U/ml) (n = 2 independently cultured replicates per group; GSE83860). Orange shading marks NF-κB p65 subunit binding site. b, ChIP-Seq enrichment of AR at the CXCL1, CXCL2, CXCL5, and CXCL12 promoters in primary human prostate cancers (n = 9 patients; GSE56288).

Extended Data Fig. 4 IL-8 Expression in Mouse and Human Prostate Cancer.

a, Representative images of positive and negative controls (cnts: murine and bacteria probe, respectively) in Myc-CaP tumors from indicated treatment groups highlight the specificity of RNA In situ hybridization independently of treatment groups. Tumors were harvested when tumor volume reached ~500mm3 (CS group) or at the time of castration-resistance (CR). Prostate tumor tissue sections were hybridized with CF568-labeled probe sets (white) to Cxcl15, CF640-labeled anti-PanCK antibody (red), and CF488-labeled anti-CD45 antibody (green). Nuclei were counterstained with DAPI (blue). b, qRT-PCR quantification of IL-8 in AR positive castration-sensitive (LNCaP, LAPC4, and VCaP) and AR independent castration-resistant (CWR22Rv1, DU145, and PC3) human prostate cancer cell lines (n = 2 independently cultured replicates per group, repeated x2). IL-8 expression levels were normalized to mean ΔCT level in DU145 samples. c, CXCL1, CXCL2, CXCL5, and CXCL12 protein expression in human AR positive castration-sensitive LNCaP cell line (CS) and it’s isogenic castration-resistant counterpart LNCaP-abl (CR) quantified by MSD (n = 3 independently cultured replicates per group, repeated x1). d, IL-8 protein expression in LNCaP and AR-independent PC3 human prostate cancer cell lines quantified by MSD, replicates as in c. e, Treatment scheme for GFP induction with Doxycycline (DOX) in transgenic Hoxb13-rtTA | TetO-H2BGFP mice for specific isolation of benign murine prostate epithelial cells from castration-sensitive (CS), androgen-deprivation treated (pADT) non-tumor bearing mice, and ADT-treated mice that received testosterone repletion (pADT + T). f, IL-8-RISH quantification in human prostate tumor specimens from untreated (n = 20 patients) or ADT-treated (n = 15 patients; NCT01696877). Quantification was restricted to tumor areas and represented as number of positive cells per mm2. Images representative of 3 independent experiments. RISH images are 60X magnification; scale bar=100 μm. For b, Tukey’s multiple comparisons test with a single pooled variance was performed, p-values ≤ 0.0001 (****). Bar plots represent means with SEM. Unpaired two-tailed (c-d) t-tests were performed, p-values ≤ 0.0001 (****); p-values ≥ 0.05 (ns). For f a Mann-Whitney U test was used due to the non-normal data distribution observed. The box plot includes 25th to 75th of all IL-8 positive cells/mm2 values with horizontal line indicating the median values. The whiskers represent the highest values, including outliers and extremes.

Source data

Extended Data Fig. 5 PMN-MDSCs Infiltration Relays on IL-8 (Cxcl15) / CXCR2 Signaling Following ADT.

a, PMN-MDSCs as a percentage of CD45+ cells in the TME of indicated human prostate tumors as determined by flow cytometry (n = 3 LNCaP and n = 6 PC3 tumors per group, 2 independent experiments). b, Representative H&E and immunohistochemistry (Ly6G and F4/80) sections of the indicated human prostate xenografts (repeated x3). c, Dorsal prostate transgenic NPK tumors (p = 0.0493) and d, Anterior prostate transgenic NPK tumor (p = 0.0006). Left: representative H&E and immunohistochemistry of Ly6G in transgenic NPK tamoxifen-inducible prostate tumors harvested from untreated (CS group) or ADT-treated mice (CR group). CTX (degarelix) was administrated 3 months after tamoxifen-induction, and tumors were harvest 30 days later; right: Ly6G positive counts per mm2 of tumor area as described in the methods section. e, PMN-MDSC density normalized to mg of tumor weight in transgenic NPK tamoxifen-inducible prostate tumors from mice treated as described in c-d (p = 0.0208; cells/mg; n = 4 CS & n = 3 CR tumors per group). f, Left: representative H&E and immunohistochemistry of Ly6G in non-cancerous murine prostate from castration-sensitive (CS), androgen-deprivation treated (pADT) non-tumor bearing mice, and ADT-treated mice that received testosterone repletion (pADT + T). Repeated x2; right: counts of Ly6G positive cells per field as described in the methods section. g, Representative histograms of protein expression determined by flow cytometry in PMN-MDSCs from indicated organs (repeated x2). h, Representative H&E and immunohistochemistry (Ly6G and F4/80) on CR-Myc-CaP allografts treated as indicated (repeated x3). i, Representative H&E and immunohistochemistry (Ly6G and F4/80) in PC3 tumor xenografts treated as indicated (repeated x3). H&E and IHC images are 40X magnification; scale bar=50 μm. Bar plots represent means with SEM. Unpaired two-tailed (a-e) t-tests were performed, p-values ≤ 0.0001 (****); p-values ≥ 0.05 (ns). For f, Tukey’s multiple comparisons test with a single pooled variance was performed.

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Lopez-Bujanda, Z.A., Haffner, M.C., Chaimowitz, M.G. et al. Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression. Nat Cancer (2021). https://doi.org/10.1038/s43018-021-00227-3

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