Espinosa Oscar Villarreal, Awan Musaddiq, Memon Abdullah A, Frei Anne, Foeckler Jamie, Kuehn Rachel, Bruening Jennifer, Massey Becky, Wong Stuart, Shukla Monica, Kasprzak Julia, Joshi Amit, Dwinell Michael B, Himburg Heather A, Zenga Joseph
Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Head Neck. 2025 May;47(5):1379-1391. doi: 10.1002/hed.28048. Epub 2024 Dec 26.
Head and neck squamous cell carcinoma (HNSCC) presents significant treatment challenges, particularly in cases unrelated to human papillomavirus (HPV). The chemokine receptor CXCR4, interacting with its ligand CXCL12, plays a crucial role in tumor proliferation, metastasis, and treatment resistance. This study explores the therapeutic potential of engineered monomeric and dimerized CXCL12 variants (CXCL12 and CXCL12, respectively) in HNSCC and evaluates potential additive effects when combined with radiation therapy.
Clinical HNSCC biopsies were evaluated for CXCR4 expression in both previously untreated and radiorecurrent disease. HNSCC cell lines were then treated with combinations of CXCL12 variants and radiotherapy and interrogated for proliferation, gene expression change, and underlying molecular mechanisms. In vivo studies evaluated the biodistribution of engineered CXCL12 and tested these treatments in humanized cell line-derived xenograft (CDX) models.
CXCL12 significantly reduced HNSCC cell proliferation and enhanced the effects of radiotherapy, likely through biased agonism at the CXCR4 receptor and upregulation of the KISS1R pathway. In vivo, CXCL12 localized to tumor sites and augmented the effects of radiation to inhibit tumor growth.
CXCL12, in combination with radiation, demonstrates potent anti-tumor effects in HNSCC. These findings support further clinical investigation of CXCL12 to enhance the effects of radiotherapy.
头颈部鳞状细胞癌（HNSCC）带来了重大的治疗挑战，尤其是在与人类乳头瘤病毒（HPV）无关的病例中。趋化因子受体CXCR4与其配体CXCL12相互作用，在肿瘤增殖、转移和治疗抗性中发挥关键作用。本研究探讨了工程化的单体和二聚体CXCL12变体（分别为CXCL12和CXCL12）在HNSCC中的治疗潜力，并评估了与放射治疗联合使用时的潜在增效作用。
对临床HNSCC活检样本在未经治疗和放疗复发的疾病中进行CXCR4表达评估。然后用CXCL12变体与放疗的组合处理HNSCC细胞系，并对其增殖、基因表达变化和潜在分子机制进行研究。体内研究评估了工程化CXCL12的生物分布，并在人源化细胞系衍生的异种移植（CDX）模型中测试了这些治疗方法。
CXCL12显著降低了HNSCC细胞增殖，并增强了放疗效果，这可能是通过对CXCR4受体的偏向性激动作用以及KISS1R途径的上调实现的。在体内，CXCL12定位于肿瘤部位，并增强了辐射抑制肿瘤生长的效果。
CXCL12与放疗联合使用时，在HNSCC中显示出强大的抗肿瘤作用。这些发现支持对CXCL12进行进一步的临床研究，以增强放疗效果。
