Horn Lucas A, Lind Hanne, Fousek Kristen, Qin Haiyan, Rajabian Nika, Angstadt Shantel, Hsiao-Sanchez Nicole, Medina-Enriquez Miriam M, Kelly Marcus D, Allen Clint T, Hammoudeh Sarah M, Weigert Roberto, Maeda Dean Y, Zebala John A, Palena Claudia
Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
J Exp Clin Cancer Res. 2024 Dec 5;43(1):318. doi: 10.1186/s13046-024-03240-3.
Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC.
Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel.
High levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2 polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8 T cells in the combination therapy treated tumors compared to controls.
This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.
与HPV感染无关的复发性头颈部鳞状细胞癌（HNSCC）预后较差。对于免疫检查点阻断长期反应不佳的这一患者群体，需要新的方法来改善临床结局并延长生存期。本研究评估趋化因子受体CXCR1和CXCR2作为治疗HPV阴性HNSCC的潜在新靶点。
在HNSCC组织和人细胞系模型中研究IL-8、CXCR1和CXCR2的表达。使用小分子抑制剂SX-682抑制CXCR1/2，在体外和体内用人源异种移植物和HNSCC小鼠模型进行评估，既作为单一疗法，也与紫杉烷类化疗药物多西他赛联合使用。
与HPV阳性HNSCC肿瘤或细胞系相比，在HPV阴性肿瘤中观察到高水平的IL-8、CXCR1和CXCR2表达。体外使用SX-682处理HPV阴性HNSCC细胞系可使肿瘤细胞对多西他赛的细胞毒性活性敏感。在体内，用SX-682加多西他赛联合治疗HNSCC异种移植模型导致强大的抗肿瘤控制，实现肿瘤治愈。这种现象与微小RNA-200c增加及其靶标微管蛋白β-3表达降低有关，微管蛋白β-3是一种参与对微管靶向化疗耐药的蛋白质。与对照组相比，在HNSCC小鼠同基因模型中用SX-682加多西他赛进行体内治疗，通过联合治疗组肿瘤中抑制性CXCR2多形核髓源性抑制细胞同时减少和细胞毒性CD8 T细胞增加，产生强大的抗肿瘤疗效。
本研究首次报告了在HPV阴性HNSCC模型中CXCR1/2抑制与多西他赛化疗联合表现出协同作用的机制性发现。这些发现为使用这种新型联合方法治疗HPV阴性HNSCC患者以及未来CXCR1/2抑制、多西他赛和基于免疫的疗法的联合研究提供了理论依据。
