Inflammation is a hallmark of cancer1. In cancer patients, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio (NLR), associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives prostate cancer progression in humans remain unclear. Herein we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. We show that higher blood NLR reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species including myeloid chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel androgen receptor signaling inhibitor (ARSI) resistance, and if 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 ARSI-resistant mCRPC. This combination was well tolerated without dose-limiting toxicity and decreased circulating neutrophils, reduced intratumor CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration, and imparted durable clinical benefit with biochemical and radiological responses in a subset of mCRPC patients. This study provides the first clinical evidence that senescence-associated myeloid inflammation can fuel mCRPC progression and resistance to AR blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Nature. 2023 Oct 16 [Epub ahead of print]
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 de Los 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, Johann S de Bono
The Institute of Cancer Research, 15 Cotswold Road, London, UK., Northern Ireland Cancer Centre, 51 Lisburn Road, Belfast, UK., Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland., The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, UK., MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, UK., Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Institute of Oncology Research, Bellinzona, Switzerland., The Institute of Cancer Research, 15 Cotswold Road, London, UK. .