Protection against viral infections in the CNS - from human genetics to mechanistic insight
Navn på bevillingshaver
Manja Idorn
Institution
Center for Cancer Immune Therapy, Herlev Gentofte Hospital.
Beløb
DKK 880,739
År
2017
Bevillingstype
Reintegration Fellowships
Hvad?
Within the past decade, immune therapy of cancer has changed the outlook of several cancer diagnoses. Accumulating data supports the notion, that baseline tumor infiltration by activated CD8+ T cells identifies the group of patients with clinical response to treatment with immune therapy. However a large group of patients lacking tumor infiltration by T cells fails to respond to therapy. We aim to identify oncogenic signaling pathways associated with a non-T cell infiltrated tumor microenvironment, to better understand tumor immunology and the molecular mechanisms of immune evasion in metastatic melanoma.
Hvorfor?
While responses to treatment with immune therapy have been impressive, the majority of patients will eventually succumb to their disease. By identifying and deciphering oncogene pathways associated with T cell exclusion, we will better understand the induction and natural history of anti-tumor immune responses. Many oncogenes and signaling pathways are not exclusive to cancer, thus identification of specific mechanisms by which tumor intrinsic signaling can modulate immune cell priming, surveillance and resulting tumor escape, will further the understanding of the immune system as a whole. This will not only help in the identification of patients that will benefit from immune therapy, and elucidate new drug targets to potentiate immune therapy and attenuate resistance mechanisms.
Hvordan?
Human tumor samples will be surveyed for presence or absence of T cell infiltration by immunohistochemistry. In parallel, we will examine the samples for candidate oncogene pathway activation, and evaluate any potential inverse correlation between T cells and molecular pathway activation. Furthermore, bioinformatics will be used to identify additional oncogene pathways associated with immune exclusion in melanoma to reach a complete list accounting for all non-T cell infiltrated melanoma samples. To determine whether tumor intrinsic active oncogenes can causally mediate T cell exclusion, we will utilise genetically engineered mouse models of melanoma. Thus we will initiate pursuit of mechanisms responsible for diminished T cell recruitment, by flow, in vivo imaging and gene expression.