Contribution of the cutaneous APC network to melanoma progression and therapy.

描述（由申请人提供）：黑色素瘤是一种极难治疗的疾病。化疗是出了名的无效，长期缓解率可以忽略不计。最近的研究已经证实，抑制BRAF信号传导可诱导大量黑色素瘤细胞死亡，导致BRAFV600E突变检测阳性患者的应答率超过50%。不幸的是，反应是短暂的，平均持续6.8个月，最终所有患者都进展或复发。相比之下，免疫疗法可以在少数患者中产生持久的治疗效果。因此，这些方法的组合非常有吸引力。BRAF抑制诱导患者细胞死亡和黑色素瘤抗原的释放。这对黑色素瘤领域来说是令人兴奋的，因为化疗并不能可靠地杀死患者体内的黑色素瘤。最近的研究表明，垂死的肿瘤细胞可能是免疫治疗的极好抗原来源。因此，由于BRAF抑制会导致大量肿瘤细胞死亡，因此它代表了开发新型有效免疫疗法的独特机会。本研究旨在确定能够增强BRAF抑制引起的临床缓解的免疫介导策略。本文提出的研究首次全面评估了皮肤DC和巨噬细胞对BRAF抑制剂产生或缺乏治疗性免疫的贡献，使用BRAF驱动的肿瘤诱导模型。我们发现这是非常重要的，因为由于braf抑制诱导的黑色素瘤细胞死亡的内源性疫苗接种可以提供一种新的黑色素瘤免疫治疗方法。这种方法可以克服目前使用的疫苗接种策略中的许多缺点。在过去的十年中，我们的研究小组已经提供了证据，证明内源性dc的扩增及其激活可能是促进几种小鼠肿瘤模型抗肿瘤免疫的有效策略。在这里，我们建议进一步推进并测试联合BRAF抑制剂来增加肿瘤抗原可用性，以及旨在原位扩增和激活肿瘤相关CD103+ DC的疫苗接种策略，同时通过CSF-1R Ab（已经在癌症I期试验中）消除肿瘤相关的免疫抑制APC，是否可以延长对BRAF治疗的反应。BRAF抑制剂联合免疫治疗是黑色素瘤患者迫切需要的。这项研究的结果有望为设计治疗这种毁灭性疾病的关键临床试验提供理论依据。

DESCRIPTION (provided by applicant): Melanoma is an extremely difficult disease to treat. Chemotherapy is notoriously ineffective with a negligible long-term remission rate. Recent studies have established that inhibition of BRAF signaling induces massive melanoma cell death leading to response rates exceeding 50% in patients who test positive for the BRAFV600E mutation. Responses unfortunately are transient, lasting on average 6.8 months and eventually all patients' progress or relapse. In contrast, immunotherapy can produce long-lasting cures in a small minority of patients. Combination of these approaches is therefore extremely attractive. BRAF inhibition induces cell death and the release of melanoma antigens in patients. This is exciting for the melanoma field because chemotherapy does not reliably kill melanoma tumors in patients. Recent studies suggest that dying tumor cells can be excellent sources of antigen for immunotherapy. BRAF inhibition therefore, because it causes massive tumor cell death, represents a unique opportunity to develop novel effective immunotherapies. This proposal aims to identify immune mediated strategies able to potentiate clinical remissions induced by BRAF inhibition. The study proposed herein provides the first comprehensive assessment of the contribution of cutaneous DC and macrophages to the development, or the lack thereof, of therapeutic immunity to BRAF inhibitors using an inducible model of BRAF-driven tumors. We find this to be of great importance as endogenous vaccination due to BRAF-inhibition-induced melanoma cell death could offer a novel approach to melanoma immunotherapy. Such an approach could overcome numerous drawbacks in the vaccination strategies currently in use. In the last ten years, our group of investigators has provided evidence that the expansion of endogenous DCs followed by their activation might be a valid strategy to promote antitumor immunity in several mouse tumor models. Here, we propose advancing a step further and testing whether combining BRAF inhibitors to increase tumor antigen availability, together with vaccination strategies aimed at expanding and activating tumor-associated CD103+ DC in situ while eliminating tumor-associated immunosuppressive APC via CSF-1R Ab (already in cancer Phase I trial), could prolong response to BRAF therapy. Combination therapy with BRAF inhibitors and immunotherapy is urgently needed by melanoma patients. Results of this study are expected to provide a rationale for the design of key clinical trials to treat this devastating disease.