TIL dynamics in a mouse model of melanoma
Melanoma, the malignant growth of melanocytes in the skin, is a common type of skin cancer with poor prognosis. Although main treatment options are chemotherapy and radiotherapy, immunotherapy emerged recently as a promising strategy to fight against this aggressive disease. Despite extensive efforts, we are still lacking a profound understanding of the interplay between antigen-specific T-cells and the tumor microenvironment. Moreover, there is great need to better understand how immune system modulation (vaccination, immunomodulatory antibodies (Ab)) would affect T-cell infiltration into the tumor and the dynamics of the immune response. In this regard, cancer immunotherapies would benefit from biomarkers that can be used as surrogate endpoints for designing optimum immunotherapeutic regimens as well as identifying patients that would benefit most upon such treatments. This subproject focuses on discovery and validation of biomarkers related to the dynamics of the anti-tumor T-cell response using B16-OVA as a widely studied melanoma tumor model expressing ovalbumin (OVA), a traceable neo-antigen. We first aim to establish a basic kinetic tumor model to study the spontaneous interaction of tumor and the tumor-specific T-cells for identification of T-cell frequency, phenotype and location related biomarkers which can be used for mathematical modelling of the anti-tumor T-cell response (WP1). These efforts will then be further extended to study the dynamics of T-cell response in combination with immunostimulatory Abs and/or vaccines (WP2). In WP3, an already existing human TCR repertoire profiling platform will be tailored to study the mouse T-cell repertoire from WP1, WP2 and other subprojects. Using this technology, TCR-species in tumors and other compartments will then be comparatively analysed to achieve a preclinical proof of concept for identifying biomarkers related to spontaneous tumor-T-cell interplay and different immunotherapeutic interventions (WP4).
Keywords: tumor-infiltrating lymphocytes, immunotherapy, T-cell receptor repertoire, next-generation sequencing, pancreatic cancer, melanoma, vaccination, immuno-stimulatory antibodies