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Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

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dc.contributor.authorGuo, C.
dc.contributor.authorSharp, A.
dc.contributor.authorGurel, B.
dc.contributor.authorCrespo, M.
dc.contributor.authorWaugh, D.
dc.contributor.authorde Bono, J.S.
dc.date.issued2023
dc.descriptionData source: Supplementary information, https://doi.org/10.1038/s41586-023-06696-z
dc.description.abstractInflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b⁺HLA-DRˡᵒCD15⁺CD14⁻ myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
dc.identifier.citationNature, 2023; 623(7989):1053-1061
dc.identifier.doi10.1038/s41586-023-06696-z
dc.identifier.issn0028-0836
dc.identifier.issn1476-4687
dc.identifier.urihttps://hdl.handle.net/11541.2/37048
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.fundingCancer Research UK
dc.relation.fundingDOD W81XWH2110076
dc.relation.fundingLondon Movember Centre of Excellence CEO13_2-002
dc.relation.fundingPCF 19CHAL08
dc.relation.fundingVFCR C1491/A25351
dc.relation.fundingVFCR D2016-022
dc.relation.fundingWT
dc.relation.fundingRMH
dc.relation.fundingBRC
dc.relation.fundingMRC
dc.relation.fundingNIHR NF-SI-0617-10099
dc.rightsCopyright 2023 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. (http://creativecommons.org/licenses/by/4.0/.)
dc.source.urihttps://doi.org/10.1038/s41586-023-06696-z
dc.subjectchemotaxis
dc.subjecthumans
dc.subjectinflammation
dc.subjectmale
dc.subjectnitriles
dc.subjectprostate
dc.subjectdrug resistance
dc.subjectneoplasm
dc.subjectprostatic neoplasms
dc.subjectcastration-resistant
dc.subjectreceptors
dc.subjectandrogen
dc.titleTargeting myeloid chemotaxis to reverse prostate cancer therapy resistance
dc.typeJournal article
pubs.publication-statusPublished
ror.fileinfo12278579230001831 13278569150001831 Open Access Published Version
ror.mmsid9916812629701831

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