Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.
Nature
; 623(7989): 1053-1061, 2023 Nov.
Article
em En
| MEDLINE
| ID: mdl-37844613
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quimiotaxia
/
Resistencia a Medicamentos Antineoplásicos
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Células Mieloides
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Antagonistas de Receptores de Andrógenos
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Neoplasias de Próstata Resistentes à Castração
/
Antineoplásicos
Limite:
Humans
/
Male
Idioma:
En
Revista:
Nature
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Reino Unido