The role of mast cell MHC II in tumor immunosurveillance

• Applicant: Professor Dr. Tilo Biedermann
• Subject Area: Dermatology
• Term: from 2009 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 124457661

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.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1394: Mast Cells - Promoters of Health and Modulators of Disease