Islam Md Rakibul, Patel Jalpa, Back Patricia Ines, Shmeeda Hilary, Kallem Raja Reddy, Shudde Claire, Markiewski Maciej, Putnam William C, Gabizon Alberto A, La-Beck Ninh M
Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
Nano-Oncology Research Center, Oncology Institute, Shaare Zedek Medical Center, Jerusalem 9103102, Israel.
Biomolecules. 2023 Aug 26;13(9):1309. doi: 10.3390/biom13091309.
While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions, including T cell priming and activation against tumor antigens. Alendronate is a potent amino-bisphosphonate that modulates the function of macrophages in vitro, with potential as an immunotherapy if its low systemic bioavailability can be addressed. We repurposed alendronate in a non-leaky and long-circulating liposomal carrier similar to that of the clinically approved pegylated liposomal doxorubicin to facilitate rapid clinical translation. Here, we tested liposomal alendronate (PLA) as an immunotherapeutic agent for cancer in comparison with a standard of care immunotherapy, a PD-1 immune checkpoint inhibitor. We showed that the PLA induced bone marrow-derived murine non-activated macrophages and M2-macrophages to polarize towards an M1-functionality, as evidenced by gene expression, cytokine secretion, and lipidomic profiles. Free alendronate had negligible effects, indicating that liposome encapsulation is necessary for the modulation of macrophage activity. In vivo, the PLA showed significant accumulation in tumor and tumor-draining lymph nodes, sites of tumor immunosuppression that are targets of immunotherapy. The PLA remodeled the tumor microenvironment towards a less immunosuppressive milieu, as indicated by a decrease in TAM and helper T cells, and inhibited the growth of established tumors in the B16-OVA melanoma model. The improved bioavailability and the beneficial effects of PLA on macrophages suggest its potential application as immunotherapy that could synergize with T-cell-targeted therapies and chemotherapies to induce immunogenic cell death. PLA warrants further clinical development, and these clinical trials should incorporate tumor and blood biomarkers or immunophenotyping studies to verify the anti-immunosuppressive effect of PLA in humans.
虽然肿瘤相关巨噬细胞（TAM）具有促肿瘤活性，但癌症中巨噬细胞的消融可能并不理想，因为它们也具有抗肿瘤功能，包括T细胞启动和针对肿瘤抗原的激活。阿仑膦酸钠是一种有效的氨基双膦酸盐，可在体外调节巨噬细胞的功能，如果其低全身生物利用度问题能够得到解决，则具有作为免疫疗法的潜力。我们将阿仑膦酸钠重新包装在一种与临床批准的聚乙二醇化脂质体阿霉素类似的非渗漏且长循环脂质体载体中，以促进快速临床转化。在此，我们将脂质体阿仑膦酸钠（PLA）作为一种癌症免疫治疗药物与标准护理免疫疗法——一种PD-1免疫检查点抑制剂进行了比较。我们发现，PLA可诱导骨髓来源的未激活小鼠巨噬细胞和M2巨噬细胞向M1功能极化，这通过基因表达、细胞因子分泌和脂质组学谱得到了证实。游离阿仑膦酸钠的作用可忽略不计，表明脂质体包裹对于调节巨噬细胞活性是必要的。在体内，PLA在肿瘤和肿瘤引流淋巴结中显著蓄积，这些肿瘤免疫抑制部位是免疫治疗的靶点。PLA使肿瘤微环境向免疫抑制性较低的环境重塑，表现为TAM和辅助性T细胞减少，并抑制了B16-OVA黑色素瘤模型中已建立肿瘤的生长。PLA提高的生物利用度及其对巨噬细胞的有益作用表明其作为免疫疗法的潜在应用，可与靶向T细胞的疗法和化疗协同作用以诱导免疫原性细胞死亡。PLA值得进一步开展临床试验，并且这些临床试验应纳入肿瘤和血液生物标志物或免疫表型研究，以验证PLA在人体中的抗免疫抑制作用。
