Cellular Immunology Section, Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD.
Frederick National Laboratory for Cancer Research, Frederick, MD.
J Immunol. 2023 May 1;210(9):1428-1436. doi: 10.4049/jimmunol.2200371.
We have identified a combinational immunotherapy termed TheraVac vaccine (TheraVac) that can cure multiple large established mouse tumors, but it failed to cure melanoma in mice. TheraVac consists of an immunostimulating arm containing an agonist (HMGN1 [N1]) for TLR4 and an agonist (R848) for TLR7/8 that synergize to activate tumor-infiltrating dendritic cells (DCs) and promote Th1 immune responses. The second arm uses an immune checkpoint blockade, anti-PDL-1, to diminish tumor-associated immunosuppression. In this study, we investigated supplementation of TheraVac by a stimulator of IFN genes (STING) agonist, cyclic GMP-AMP (cGAMP), because together they synergize in activating DCs and produced more immunostimulating IL-12p70 and TNF-α cytokines. The synergistic activation and maturation of DCs is dependent on the activation of tank binding kinase-1 (TBK1). Treatment of three different melanin-producing mouse melanomas (B16F1, M3, and M4) with intratumoral delivery of cGAMP and TheraVac eradicated 60-80% of these melanomas. Immunoprofiling of M3 tumor treated with TheraVac plus cGAMP showed an increase in CD8+ CTLs and macrophages in the tumor. There was also a marked increase of CD4, CD8 effector and memory T cells and generation of functional tumor-specific CTLs in tumor-draining lymph nodes. The resultant tumor-free mice were selectively resistant to subsequent challenge with the same tumors, indicating long-term tumor-specific protective immunity. Overall, our findings have important implications for clinical trials with a combination of these immunotherapeutics to cure melanin-producing human melanomas, without the need for exogenous tumor Ags and no clear toxic effects in mice.
我们发现了一种联合免疫疗法，称为 TheraVac 疫苗（TheraVac），它可以治愈多种已建立的大型小鼠肿瘤，但未能治愈小鼠的黑色素瘤。TheraVac 由一个免疫刺激臂组成，其中包含一个 TLR4 的激动剂（HMGN1[N1]）和一个 TLR7/8 的激动剂（R848），它们协同作用激活肿瘤浸润树突状细胞（DC）并促进 Th1 免疫反应。第二臂使用免疫检查点阻断剂，抗 PD-L1，以减轻肿瘤相关的免疫抑制。在这项研究中，我们研究了用干扰素基因刺激物（STING）激动剂，环鸟苷酸-腺苷酸（cGAMP）补充 TheraVac，因为它们共同协同激活 DC，并产生更多的免疫刺激 IL-12p70 和 TNF-α细胞因子。DC 的协同激活和成熟依赖于 Tank 结合激酶-1（TBK1）的激活。用肿瘤内递送 cGAMP 和 TheraVac 治疗三种不同的黑色素瘤（B16F1、M3 和 M4），可根除 60-80%的这些黑色素瘤。用 TheraVac 加 cGAMP 治疗的 M3 肿瘤的免疫分析显示肿瘤中 CD8+CTL 和巨噬细胞增加。肿瘤引流淋巴结中还观察到 CD4、CD8 效应和记忆 T 细胞的明显增加，以及功能性肿瘤特异性 CTL 的产生。无肿瘤的小鼠对随后相同肿瘤的再次攻击具有选择性抗性，表明具有长期的肿瘤特异性保护免疫。总的来说，我们的发现对于临床试验具有重要意义，即联合使用这些免疫疗法来治疗产生黑色素的人类黑色素瘤，而无需外源性肿瘤抗原，并且在小鼠中没有明显的毒性作用。
