Division of Cellular Signaling, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan.
Cancer Sci. 2024 Sep;115(9):2879-2892. doi: 10.1111/cas.16251. Epub 2024 Jun 18.
Programmed death 1 (PD-1)/programmed death-ligand 1 inhibitors are commonly used to treat various cancers, including melanoma. However, their efficacy as monotherapy is limited, and combination immunotherapies are being explored to improve outcomes. In this study, we investigated a combination immunotherapy involving an anti-PD-1 antibody that blocks the major adaptive immune-resistant mechanisms, a BRAF inhibitor that inhibits melanoma cell proliferation, and multiple primary immune-resistant mechanisms, such as cancer cell-derived immunosuppressive cytokines, and a Toll-like receptor 7 agonist that enhances innate immune responses that promote antitumor T-cell induction and functions. Using a xenogeneic nude mouse model implanted with human BRAF-mutated melanoma, a BRAF inhibitor vemurafenib was found to restore T-cell-stimulatory activity in conventional dendritic cells by reducing immunosuppressive cytokines, including interleukin 6, produced by human melanoma. Additionally, intravenous administration of the Toll-like receptor 7 agonist DSR6434 enhanced tumor growth inhibition by vemurafenib through stimulating the plasmacytoid dendritic cells/interferon-α/natural killer cell pathways and augmenting the T-cell-stimulatory activity of conventional dendritic cells. In a syngeneic mouse model implanted with murine BRAF-mutated melanoma, the vemurafenib and DSR6434 combination synergistically augmented the induction of melanoma antigen gp100-specific T cells and inhibited tumor growth. Notably, only triplet therapy with vemurafenib, DSR6434, and the anti-PD-1 antibody resulted in complete regression of SIY antigen-transduced BRAF-mutated melanoma in a CD8 T-cell-dependent manner. These findings indicate that a triple-combination strategy targeting adaptive and primary resistant mechanisms while enhancing innate immune responses that promote tumor-specific T cells may be crucial for effective tumor eradication.
程序性死亡受体 1（PD-1）/程序性死亡配体 1 抑制剂常用于治疗各种癌症，包括黑色素瘤。然而，它们作为单一疗法的疗效有限，因此正在探索联合免疫疗法以改善疗效。在这项研究中，我们研究了一种联合免疫疗法，该疗法涉及一种抗 PD-1 抗体，该抗体可阻断主要的适应性免疫抵抗机制；一种 BRAF 抑制剂，该抑制剂可抑制黑色素瘤细胞的增殖以及多种原发性免疫抵抗机制，如癌细胞衍生的免疫抑制细胞因子；一种 Toll 样受体 7 激动剂，可增强促进抗肿瘤 T 细胞诱导和功能的先天免疫反应。使用植入人 BRAF 突变黑色素瘤的异种裸鼠模型，发现 BRAF 抑制剂 vemurafenib 通过减少包括白细胞介素 6 在内的免疫抑制细胞因子的产生，恢复了常规树突状细胞的 T 细胞刺激活性，这些细胞因子由人黑色素瘤产生。此外，静脉内给予 Toll 样受体 7 激动剂 DSR6434 通过刺激浆细胞样树突状细胞/干扰素-α/自然杀伤细胞途径和增强常规树突状细胞的 T 细胞刺激活性来增强 vemurafenib 的肿瘤生长抑制作用。在植入鼠 BRAF 突变黑色素瘤的同基因小鼠模型中，vemurafenib 和 DSR6434 联合治疗协同增强了黑色素瘤抗原 gp100 特异性 T 细胞的诱导，并抑制了肿瘤生长。值得注意的是，只有 vemurafenib、DSR6434 和抗 PD-1 抗体的三联疗法才能以 CD8 T 细胞依赖性方式导致转导 SIY 抗原的 BRAF 突变黑色素瘤完全消退。这些发现表明，针对适应性和原发性抵抗机制的三联组合策略，同时增强促进肿瘤特异性 T 细胞的先天免疫反应，可能是有效肿瘤消除的关键。
