Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

作者：Christina W. Guo, Adam Sharp, Bora Gürel, Mateus Crespo, Inês Ferreira Figueiredo, Suneil Jain, Ursula Maria Vogl, Jan Rekowski, Mahtab Rouhifard, Lewis Gallagher, Wei Yuan, Suzanne Carreira, Khobe Chandran, Alec Paschalis, Ilaria Colombo, Anastasios Stathis, Claudia Maria Bertan, George Seed, JANE C. GOODALL, Florence I. Raynaud, Ruth R. Ruddle, Karen E. Swales, Jason Malia, Denisa Bogdan, Crescens Tiu, Reece Caldwell, Caterina Aversa, Ana Júllia Almeida Ferreira, Antje Neeb, Nina Tunariu, Daniel Westaby, Juliet A. Carmichael, Maria D. Fenor de la Maza, Christina Gertrude Yap, Ruth Matthews, Hannah Badham, Toby Prout, Alison Turner, Mona Parmar, Holly Tovey, Ruth Riisnaes, Penny Flohr, Jesús Gil, David J J Waugh, Shaun Decordova, Anna Schlag, Bianca Calì, Andrea Alimonti, Johann Sebastian De Bono · 发表于：Nature · 年份：2023 · DOI：10.1038/s41586-023-06696-z · 被引用次数：136 · 研究领域：Chemokine receptors and signaling、Prostate Cancer Treatment and Research、Inflammatory Biomarkers in Disease Prognosis

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. T...