Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.
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Embargo End Date
ICR Authors
Sharp, Adam
Gurel, Bora
Figueiredo, Ines
Rekowski, Jan
Gallagher, Lewis
Yuan, Wei
Carreira, Suzanne
Paschalis, Alec
Seed, George
Raynaud, Florence
Ruddle, Ruth
Swales, Karen
Bogdan, Denisa Ioana
Tiu, Crescens
Tunariu, Nina
Westaby, Daniel
Carmichael, Juliet
Yap, Christina
Tovey, Holly
De Bono, Johann
Gurel, Bora
Figueiredo, Ines
Rekowski, Jan
Gallagher, Lewis
Yuan, Wei
Carreira, Suzanne
Paschalis, Alec
Seed, George
Raynaud, Florence
Ruddle, Ruth
Swales, Karen
Bogdan, Denisa Ioana
Tiu, Crescens
Tunariu, Nina
Westaby, Daniel
Carmichael, Juliet
Yap, Christina
Tovey, Holly
De Bono, Johann
Authors
Guo, C
Sharp, A
Gurel, B
Crespo, M
Figueiredo, I
Jain, S
Vogl, U
Rekowski, J
Rouhifard, M
Gallagher, L
Yuan, W
Carreira, S
Chandran, K
Paschalis, A
Colombo, I
Stathis, A
Bertan, C
Seed, G
Goodall, J
Raynaud, F
Ruddle, R
Swales, KE
Malia, J
Bogdan, D
Tiu, C
Caldwell, R
Aversa, C
Ferreira, A
Neeb, A
Tunariu, N
Westaby, D
Carmichael, J
Fenor de la Maza, MD
Yap, C
Matthews, R
Badham, H
Prout, T
Turner, A
Parmar, M
Tovey, H
Riisnaes, R
Flohr, P
Gil, J
Waugh, D
Decordova, S
Schlag, A
Calì, B
Alimonti, A
de Bono, JS
Sharp, A
Gurel, B
Crespo, M
Figueiredo, I
Jain, S
Vogl, U
Rekowski, J
Rouhifard, M
Gallagher, L
Yuan, W
Carreira, S
Chandran, K
Paschalis, A
Colombo, I
Stathis, A
Bertan, C
Seed, G
Goodall, J
Raynaud, F
Ruddle, R
Swales, KE
Malia, J
Bogdan, D
Tiu, C
Caldwell, R
Aversa, C
Ferreira, A
Neeb, A
Tunariu, N
Westaby, D
Carmichael, J
Fenor de la Maza, MD
Yap, C
Matthews, R
Badham, H
Prout, T
Turner, A
Parmar, M
Tovey, H
Riisnaes, R
Flohr, P
Gil, J
Waugh, D
Decordova, S
Schlag, A
Calì, B
Alimonti, A
de Bono, JS
Document Type
Journal Article
Date
2023-11-30
Date Accepted
2023-09-28
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.
Citation
Nature, 2023, 623 (7989), pp. 1053 - 1061
Source Title
Nature
Publisher
NATURE PORTFOLIO
ISSN
0028-0836
eISSN
1476-4687
1476-4687
1476-4687
Collections
Research Team
Cancer Biomarkers
Clinical Pharma & Trials
Clin PD Biomarker Group
Cell Death and Immunity
Clin Trials & Stats Unit
PrCa Targeted Therapy
Clinical Pharma & Trials
Clin PD Biomarker Group
Cell Death and Immunity
Clin Trials & Stats Unit
PrCa Targeted Therapy