UPMC Hillman Cancer Center, Division of Malignant Hematology and Medical Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Int J Mol Sci. 2024 Nov 15;25(22):12277. doi: 10.3390/ijms252212277.
Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11bLy6GLy6C myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction.
头颈部鳞状细胞癌 (HNSCC) 富含浸润性髓系细胞，包括肿瘤相关巨噬细胞 (TAMs) 和髓系来源的抑制细胞 (MDSCs)。然而，目前缺乏针对 HNSCC 中肿瘤相关髓系细胞的有效治疗药物。在这里，我们采用了一种独特的共培养系统来研究 HNSCC 细胞如何影响肿瘤相关髓系细胞。我们发现癌细胞的存在显著增强了髓系细胞的增殖，并促进了 TAM 的分化。为了确定潜在的治疗药物，我们筛选了一个包含 70 种激酶抑制剂的定制文库，以评估它们对不同肿瘤相关髓系细胞亚群的影响。我们发现了一些特定的抑制剂，可以有区别地抑制 TAMs、单核来源的 MDSCs (M-MDSCs) 或多形核 MDSCs (PMN-MDSCs) 的群体，表明抑制不同的靶点可以减少不同肿瘤相关髓系细胞亚群。相反，一些抑制剂被发现增加了 CD11bLy6GLy6C 髓系细胞的群体。在测试的有前途的抑制剂中，VEGF-R 抑制剂伐他拉尼在体内抑制肿瘤生长和减少肿瘤相关髓系细胞方面表现出显著疗效，强调了其作为治疗药物的潜力。我们的研究结果突出了具有差异调节 HNSCC 相关髓系亚群作用的特定激酶抑制剂，并警告一些抑制剂作为抗癌药物的应用。该实验系统可能为识别针对 HNSCC 中肿瘤相关髓系细胞的新药物以及阐明肿瘤-髓系细胞相互作用的机制提供一个强大的平台。
