Thesis supervisor: Lajos Vince Kemény
Location of studies (in Hungarian): Semmelweis Egyetem Abbreviation of location of studies: SE
Description of the research topic:
Overall aim of the project
Despite recent developments in the field of immune-oncology by the introduction of immune-checkpoint blockade (ICB) in the management of melanoma, resistance to ICB therapies still poses a tremendous problem. The most common resistance mechanism, the loss of antigen presentation, might offer novel vulnerabilities to antigen presentation-independent mechanisms. In this proposal we aim to identify novel therapeutic approaches to overcome resistance to ICB therapies. We plan to find regulators and novel therapeutic targets in melanoma models of antigen presentation deficiency by performing in vivo genome-wide crispr screen. The PhD project may provide a better mechanistic understanding of melanoma-immune cell interactions and offers immediate translational relevance.
Unresolved problems
A huge unmet clinical need is to identify additional therapeutic targets that can either prevent or overcome intrinsic and acquired resistance to ICB.
The most important mechanism of resistance to ICB therapies is the reduced presentation of self-antigens or neoantigens due to decreased expression or mutations in MHC-I genes (Sade-Feldman et al., 2017). Tumor cells that do not present their own self-antigens or neoantigens on MHC-I proteins do not respond to cytotoxic CD8 T cells (and thus to ICB therapies). Therefore, overcoming resistance mechanisms associated with diminished antigen presentation on tumor cells might carry potential benefit for patients with intrinsic or acquired resistance to ICB blockade.
Main hypothesis
Here, we hypothesize that in the absence of MHC-I presentation, additional, CD8 independent mechanisms could be utilized in the management of melanoma.
Main Tasks
Task 1. Creating and optimizing a mouse model of melanoma with intrinsic resistance to immune checkpoint-blockade due to insuffifient antigen presentation.
Task 2. Performing the genome wide-crispr screen in various mouse models of melanoma.
Task 3. Mechanistic understanding of the function of genes identified in Task 2. Expected timeframe: years 3 and 4.
Deadline for application: 2024-06-30
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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