%0 Journal Article
%T Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.
%A Guo C
%A Sharp A
%A Gurel B
%A Crespo M
%A Figueiredo I
%A Jain S
%A Vogl U
%A Rekowski J
%A Rouhifard M
%A Gallagher L
%A Yuan W
%A Carreira S
%A Chandran K
%A Paschalis A
%A Colombo I
%A Stathis A
%A Bertan C
%A Seed G
%A Goodall J
%A Raynaud F
%A Ruddle R
%A Swales KE
%A Malia J
%A Bogdan D
%A Tiu C
%A Caldwell R
%A Aversa C
%A Ferreira A
%A Neeb A
%A Tunariu N
%A Westaby D
%A Carmichael J
%A Fenor de la Maza MD
%A Yap C
%A Matthews R
%A Badham H
%A Prout T
%A Turner A
%A Parmar M
%A Tovey H
%A Riisnaes R
%A Flohr P
%A Gil J
%A Waugh D
%A Decordova S
%A Schlag A
%A Calì B
%A Alimonti A
%A de Bono JS
%J Nature
%V 623
%N 7989
%D 2023 Nov 16
%M 37844613
%F 69.504
%R 10.1038/s41586-023-06696-z
%X 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.