A TLR7 agonist strengthens T and NK cell function during BRAF-targeted therapy in a preclinical melanoma model
A TLR7 agonist strengthens T and NK cell function during BRAF-targeted therapy in a preclinical melanoma model
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DOI：
10.1002/ijc.32777
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发表时间：
2019-12-04
影响因子：
6.4
通讯作者：
Stoitzner, Patrizia
中科院分区：
文献类型：
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作者：
Bellmann, Lydia;Cappellano, Giuseppe;Stoitzner, Patrizia
BRAF抑制剂（BRAFi）靶向治疗黑色素瘤的治疗成功受到耐药性发展的限制。来自临床前小鼠模型的观察和最近对BRAFi引起的免疫学效应的见解为人类黑色素瘤联合治疗的未来发展提供了希望。在我们的研究中，我们使用具有BRAF（V600 E）突变和伴随的PTEN损失的可移植D4 M黑素瘤小鼠模型，以表征当肿瘤变得对BRAFi具有抗性时肿瘤浸润效应免疫细胞的改变。我们发现，BRAFi敏感性肿瘤显示出明显的炎症环境，其特征在于高水平的细胞因子和趋化因子伴随着T和NK细胞的浸润。肿瘤浸润效应细胞被激活并产生高水平的IFN-γ、TNF-α和颗粒酶B。当肿瘤变得耐药并逐渐生长时，它们恢复到与未治疗的肿瘤相似的低免疫原性状态，如促炎细胞因子和趋化因子的低mRNA水平以及较少的肿瘤浸润性T和NK细胞所反映的。此外，这些T和NK细胞与BRAFi敏感性肿瘤中的对应物相比功能受损。他们的效应细胞功能可以恢复额外的肿瘤周围治疗与TLR 7激动剂咪喹莫特，临床批准的非黑色素瘤皮肤癌的代理。事实上，对BRAFi治疗的抗性被延迟，并伴随着肿瘤中大量活化的T和NK细胞。因此，将BRAFi与免疫刺激剂如TLR配体组合可能是治疗黑色素瘤的有希望的替代方法。
Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAF(V600E) mutation and concomitant PTEN loss in order to characterize alterations in tumor-infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi-sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor-infiltrating effector cells were activated and produced high levels of IFN-gamma, TNF-alpha and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor-infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi-sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.