The role of mast cell MHC II in tumor immunosurveillance

黑色素瘤可以表现出自发的免疫消退，因此被认为是研究癌症免疫治疗的有用模型。然而，启动黑色素瘤消退的连续步骤并不具有特征性。肥大细胞(MC)和树突状细胞(DC)是兼具促炎和调节功能的免疫调节剂，MC在黑色素瘤中积聚，特别是在黑色素瘤周围自发免疫消退。事实上，我们发现MC缺陷的KitW-sh和KitW/KitW-v小鼠比野生型小鼠发展出更大的黑色素瘤，这可以通过先前的MC重建来逆转。通过对其潜在机制的研究，我们发现DC中的MHC II分子在体外和体内都能迅速转移到MC。重要的是，DC还可以将多肽负载的MHC II转移到MC和MHC II+MC，但不能将MHC II-MC激活抗原经历的CD4+T辅助细胞(Th)，显著上调TNF、IL-6和IL-17。值得注意的是，皮肤黑色素瘤中80%的MC是MHC II+MC，而在未经治疗或过敏性接触性皮炎的皮肤中，这一比例仅为30%。本项目第二阶段的目标是进一步研究MHC II从DC转移到MC的机制，确定这一效应的体内动力学和可持续性，并表征MHCII+MC与Th细胞相互作用对MC和T细胞生物学和免疫功能的影响。最重要的是，MHCII+MC在黑色素瘤免疫监控方面的体内功能后果将使用各种模型进行评估，以使我们也能够评估我们发现的翻译潜力。

Melanoma can show spontaneous immune regression and consequently is considered a useful model to investigate cancer immuno-therapy. However, the consecutive steps initiating melanoma regression are not characterized. Mast cells (MC) and dendritic cells (DC) are immune modulators with both pro-inflammatory and regulatory potential and MC accumulate especially in and around melanomas with spontaneous immune regression. Indeed, we found that MC deficient KitW-sh and KitW/KitW-v mice develop larger melanomas compared to wildtype mice, which could be reverted by previous MC reconstitution. Investigating underlying mechanisms, we identified that MHC II molecules from DC are rapidly transferred to MC both in vitro and in vivo. Importantly, DC can transfer also peptide loaded MHC II to MC and MHC II+ MC but not MHC II- MC activate antigen-experienced CD4+ T helper (Th) cells, significantly upregulating TNF, IL-6 and IL-17. Strikingly, 80% of MC in cutaneous melanoma were MHC II+ MC compared to only 30% in untreated or allergic contact dermatitis skin. The objectives of the second term of this project are to further characterize the mechanisms of MHC II transfer from DC to MC, to determine the in vivo dynamics and sustainability of this effect and to characterize the impact of MHCII+ MC interactions with Th cells for both MC and T cell biology and immune function. Most importantly, functional in vivo consequences of MHCII+ MC in regard to melanoma immunosurveillance will be assessed using a variety of models to allow us to also evaluate the translational potential of our findings.