Increasing evidence shows that the CXC chemokine receptor 2 (CXCR2) signaling pathway is essentially implicated in the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and leads to MDSC-mediated immune suppression. Therefore, CXCR2 has recently emerged as a promising drug target for cancer immunotherapy. In this paper, benzocyclic sulfone derivatives were designed as potent CXCR2 antagonists. Structure–activity relationship studies resulted in two lead compounds 9b and 11h, which demonstrated double-digit nanomolar potencies against CXCR2 and significantly inhibited neutrophil infiltration into the air pouch in an in vivo setting. More importantly, 9b and 11h dose-dependently inhibited the tumor growth through oral administration in the Pan02 mouse model. Further cytometry and immunohistochemical analyses revealed that 9b and 11h could reduce the infiltration of neutrophils and MDSCs and enhance the infiltration of CD3⁺ T lymphocytes into the Pan02 tumor tissues, shedding light on their mechanisms of action in cancer immunotherapy.

中文翻译：

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发现苯环砜衍生物作为癌症免疫治疗的强效 CXCR2 拮抗剂

越来越多的证据表明，CXC 趋化因子受体 2 (CXCR2) 信号通路本质上与骨髓来源的抑制细胞 (MDSC) 向肿瘤微环境的募集有关，并导致 MDSC 介导的免疫抑制。因此，CXCR2最近已成为癌症免疫治疗的有希望的药物靶点。在本文中，苯环砜衍生物被设计为有效的 CXCR2 拮抗剂。结构-活性关系研究产生了两种先导化合物9b和11h ，它们在体内环境中显示出对 CXCR2 的两位数纳摩尔效力并显着抑制中性粒细胞浸润到气囊中。更重要的是9b和11h在 Pan02 小鼠模型中，通过口服给药剂量依赖性地抑制肿瘤生长。进一步的细胞计数和免疫组织化学分析表明，9b和11h可以减少中性粒细胞和 MDSC 的浸润，并增强 CD3 ⁺ T 淋巴细胞向 Pan02 肿瘤组织的浸润，从而阐明它们在癌症免疫治疗中的作用机制。