dc.contributor.author | Guo, C | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Jain, S | |
dc.contributor.author | Vogl, U | |
dc.contributor.author | Rekowski, J | |
dc.contributor.author | Rouhifard, M | |
dc.contributor.author | Gallagher, L | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Chandran, K | |
dc.contributor.author | Paschalis, A | |
dc.contributor.author | Colombo, I | |
dc.contributor.author | Stathis, A | |
dc.contributor.author | Bertan, C | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Goodall, J | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Ruddle, R | |
dc.contributor.author | Swales, KE | |
dc.contributor.author | Malia, J | |
dc.contributor.author | Bogdan, D | |
dc.contributor.author | Tiu, C | |
dc.contributor.author | Caldwell, R | |
dc.contributor.author | Aversa, C | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Neeb, A | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Westaby, D | |
dc.contributor.author | Carmichael, J | |
dc.contributor.author | Fenor de la Maza, MD | |
dc.contributor.author | Yap, C | |
dc.contributor.author | Matthews, R | |
dc.contributor.author | Badham, H | |
dc.contributor.author | Prout, T | |
dc.contributor.author | Turner, A | |
dc.contributor.author | Parmar, M | |
dc.contributor.author | Tovey, H | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Flohr, P | |
dc.contributor.author | Gil, J | |
dc.contributor.author | Waugh, D | |
dc.contributor.author | Decordova, S | |
dc.contributor.author | Schlag, A | |
dc.contributor.author | Calì, B | |
dc.contributor.author | Alimonti, A | |
dc.contributor.author | de Bono, JS | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-01-08T11:23:04Z | |
dc.date.available | 2024-01-08T11:23:04Z | |
dc.date.issued | 2023-11-30 | |
dc.identifier | 10.1038/s41586-023-06696-z | |
dc.identifier.citation | Nature, 2023, 623 (7989), pp. 1053 - 1061 | |
dc.identifier.issn | 0028-0836 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6095 | |
dc.identifier.eissn | 1476-4687 | |
dc.identifier.eissn | 1476-4687 | |
dc.identifier.doi | 10.1038/s41586-023-06696-z | |
dc.identifier.doi | 10.1038/s41586-023-06696-z | |
dc.description.abstract | Inflammation is a hallmark of cancer1. 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 modalities2-5. 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.format | Print-Electronic | |
dc.format.extent | 1053 - 1061 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.ispartof | Nature | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Humans | |
dc.subject | Male | |
dc.subject | Chemotaxis | |
dc.subject | Disease Progression | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Inflammation | |
dc.subject | Lewis X Antigen | |
dc.subject | Myeloid Cells | |
dc.subject | Neoplasm Metastasis | |
dc.subject | Prostate | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.subject | Receptors, Androgen | |
dc.subject | Androgen Receptor Antagonists | |
dc.subject | Antineoplastic Agents | |
dc.title | Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-09-28 | |
dc.date.updated | 2024-01-03T00:55:25Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41586-023-06696-z | |
rioxxterms.licenseref.startdate | 2023-11-30 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37844613 | |
pubs.issue | 7989 | |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Breast Cancer Research/Cell Death and Immunity | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/20/21 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/21/22 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/22/23 Starting Cohort | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41586-023-06696-z | |
pubs.volume | 623 | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical Pharma & Trials | |
icr.researchteam | Clin PD Biomarker Group | |
icr.researchteam | Cell Death and Immunity | |
icr.researchteam | Clin Trials & Stats Unit | |
icr.researchteam | PrCa Targeted Therapy | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Gallagher, Lewis | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Ruddle, Ruth | |
dc.contributor.icrauthor | Swales, Karen | |
dc.contributor.icrauthor | Bogdan, Denisa Ioana | |
dc.contributor.icrauthor | Tiu, Crescens | |
dc.contributor.icrauthor | Westaby, Daniel | |
dc.contributor.icrauthor | Yap, Christina | |
dc.contributor.icrauthor | Tovey, Holly | |
dc.contributor.icrauthor | De Bono, Johann | |
icr.provenance | Deposited by Prof Christina Yap on 2024-01-03. Deposit type is initial. No. of files: 1. Files: Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.pdf | |