Unlike several other tumor types, prostate cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate cancer progression and resistance to ICB, we analyzed prostate cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog Cxcl15 in prostate epithelial cells. We showed that these chemokines drove subsequent intratumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration, and highlight blockade of the IL-8/CXCR2 axis as a potential therapeutic intervention.

与其他几种肿瘤类型不同，前列腺癌很少对免疫检查点阻断 (ICB) 产生反应。为了确定导致前列腺癌进展和对 ICB 耐药的肿瘤细胞内在因素，我们使用植入肿瘤、细胞系、转基因模型和人体组织分析了来自去势敏感和耐药样本的前列腺癌上皮细胞。我们发现去势导致前列腺上皮细胞中白介素 8 (IL-8) 及其可能的鼠同源物 Cxcl15 的表达增加。我们发现，这些趋化因子随后驱动肿瘤促进多形核骨髓源性抑制细胞（PMN-MDSC）的瘤内浸润，当通过基因或药理学阻断IL-8信号传导时，这种浸润在很大程度上被消除。靶向 IL-8 信号传导与 ICB 相结合可延迟去势抵抗的发生并增加肿瘤中多功能 CD8 T 细胞的密度。我们的研究结果建立了一种新机制，通过该机制去势介导 IL-8 分泌和随后的 PMN-MDSC 浸润，并强调阻断 IL-8/CXCR2 轴作为潜在的治疗干预。