Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Christina Guo, Adam Sharp, Bora Gurel, Mateus Crespo, Ines Figueiredo, Suneil Jain, Ursula Vogl, Jan Rekowski, Mahtab Rouhifard, Lewis Gallagher, Wei Yuan, Suzanne Carreira, Khobe Chandran, Alec Paschalis, Ilaria Colombo, Anastasios Stathis, Claudia Bertan, George Seed, Jane Goodall, Florence Raynaud, Ruth Ruddle, Karen E. Swales, Jason Malia, Denisa Bogdan, Crescens Tiu, Reece Caldwell, Caterina Aversa, Ana Ferreira, Antje Neeb, Nina Tunariu, Daniel Westaby, Juliet Carmichael, Maria Dolores Fenor de la Maza, Christina Yap, Ruth Matthews, Hannah Badham, Toby Prout, Alison Turner, Mona Parmar, Holly Tovey, Ruth Riisnaes, Penny Flohr, Jesus Gil, David Waugh, Shaun Decordova, Anna Schlag, Bianca Calì, Andrea Alimonti and Johann S. Bono ()
Additional contact information
Christina Guo: The Institute of Cancer Research
Adam Sharp: The Institute of Cancer Research
Bora Gurel: The Institute of Cancer Research
Mateus Crespo: The Institute of Cancer Research
Ines Figueiredo: The Institute of Cancer Research
Suneil Jain: Northern Ireland Cancer Centre
Ursula Vogl: Ente Ospedaliero Cantonale (EOC)
Jan Rekowski: The Institute of Cancer Research
Mahtab Rouhifard: The Institute of Cancer Research
Lewis Gallagher: The Institute of Cancer Research
Wei Yuan: The Institute of Cancer Research
Suzanne Carreira: The Institute of Cancer Research
Khobe Chandran: The Institute of Cancer Research
Alec Paschalis: The Institute of Cancer Research
Ilaria Colombo: Ente Ospedaliero Cantonale (EOC)
Anastasios Stathis: Ente Ospedaliero Cantonale (EOC)
Claudia Bertan: The Institute of Cancer Research
George Seed: The Institute of Cancer Research
Jane Goodall: The Institute of Cancer Research
Florence Raynaud: The Institute of Cancer Research
Ruth Ruddle: The Institute of Cancer Research
Karen E. Swales: The Institute of Cancer Research
Jason Malia: The Institute of Cancer Research
Denisa Bogdan: The Institute of Cancer Research
Crescens Tiu: The Institute of Cancer Research
Reece Caldwell: The Royal Marsden NHS Foundation Trust
Caterina Aversa: The Royal Marsden NHS Foundation Trust
Ana Ferreira: The Institute of Cancer Research
Antje Neeb: The Institute of Cancer Research
Nina Tunariu: The Royal Marsden NHS Foundation Trust
Daniel Westaby: The Institute of Cancer Research
Juliet Carmichael: The Institute of Cancer Research
Maria Dolores Fenor de la Maza: The Institute of Cancer Research
Christina Yap: The Institute of Cancer Research
Ruth Matthews: The Institute of Cancer Research
Hannah Badham: The Institute of Cancer Research
Toby Prout: The Institute of Cancer Research
Alison Turner: The Institute of Cancer Research
Mona Parmar: The Institute of Cancer Research
Holly Tovey: The Institute of Cancer Research
Ruth Riisnaes: The Institute of Cancer Research
Penny Flohr: The Institute of Cancer Research
Jesus Gil: MRC London Institute of Medical Sciences (LMS)
David Waugh: Queen’s University Belfast
Shaun Decordova: The Institute of Cancer Research
Anna Schlag: The Institute of Cancer Research
Bianca Calì: Institute of Oncology Research
Andrea Alimonti: Ente Ospedaliero Cantonale (EOC)
Johann S. Bono: The Institute of Cancer Research

Nature, 2023, vol. 623, issue 7989, 1053-1061

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06696-z

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