Melanoma immune surveillance in the epidermal niche
Most cancers originate within epithelial tissues, including all carcinomas and melanoma. Of note, tissue-resident memory T cells (TRM) dominate immunity in these anatomical compartments, whereas circulating T cells are largely excluded from epithelial tissues in absence of inflammation. This implies an important role for TRM in epithelial cancer surveillance and this notion is further supported by emerging clinical data that link tumour-associated TRM with improved survival in cancer patients. Yet, a direct proof-of-principle for a protective function of TRM in cancer surveillance is missing.
To address this issue, we have developed a model of transplantable B16 melanoma that approximates skin-contained tumour development and permits the analysis of CD4+ and CD8+ T-cell responses to model neoantigens. Importantly, this model recapitulates distinct disease stages seen in patients, including progressively growing or stably controlled tumours, as well as long-term persistence of melanoma cells in absence of macroscopic tumours. Of note, the latter two stages reflect the establishment of a local ‘melanoma-immune equilibrium’ that can be maintained for several months.
We will use this model to dissect the role of circulating and skin-resident memory CD4+ and CD8+ T cells in long-term melanoma control. We will further define their protective effector functions and how these are regulated by epidermal and lymphoid-resident antigen presenting cells such as Langerhans cells, dendritic cells and myeloid cells. The overall goal of our studies is to reveal fundamental mechanisms in epidermal melanoma immune surveillance and as such, may provide new avenues for the improvement of current cancer immunotherapies.
Tissue-resident cytotoxic T memory cells in skin melanoma
Cytotoxic CD8+ T cells provide protection against certain recurrent viral infections such as herpes simplex virus (HSV) and also play an important role in the control of malignant tumours such as melanoma in the skin. The regulation of T cell effector functions against virally infected or transformed cells share many similarities. In fact, modern tumour immunotherapy targeting the PD1/PDL1 immune check point is rooted in part on insights gained in mouse models for viral infection. Currently, the exact cellular mechanisms involved in maintaining long-lived immune surveillance within peripheral tissues such as the skin are largely unknown. In order to address this important issue, this project combines our expertise in skin immunology/oncology (Tüting), skin immunology/virology (Gebhardt) and tumour biology/genome engineering (Hölzel). We will utilise and further develop genetically engineered mouse models that combine tumour biology and tumour immunology and involve immunotherapy approaches with tumour–specific cytotoxic CD8+ T cells. Employing this model, we will determine the role of a recently described population of permanently tissue–resident cytotoxic T memory (TRM) cells in melanoma growth surveillance. We will analyse the interactions between melanoma cells and melanoma–specific TRM cells and will define the role of professional antigen–presenting cells such as myeloid–derived epidermal Langerhans cells and dermal dendritic cells in local TRM cell activation and melanoma surveillance. While most of our work will rely on the use of well–defined genetic mouse models, we will validate key findings with patient material derived from skin biopsies and surgery specimens. Our results will provide novel insights into immune mechanisms underlying the long-term control of skin cancers, and as such will have the potential to identify innovative avenues for future immunotherapies.