Group Leader: Emile Voest Voest group
PD-1 blockade has revolutionized the treatment of many malignancies, including mismatch repair deficient (MMR-d) cancers. The established mechanism of action dictates that PD-1 blockade boosts endogenous antitumor immunity driven by CD8+ T cells, which in turn recognize Human Leukocyte Antigen (HLA) class I-bound neoepitopes on cancer cells. However, mismatch repair deficient (MMR-d) colon cancers frequently lose HLA class I-mediated antigen presentation due to silencing of HLA class I genes, inactivating mutations in b2-microglobulin (B2M), or other defects in the antigen processing machinery, which renders these tumors resistant to conventional CD8+ T cell-mediated immunity. However, our group has recently discovered that MMR-d cancers with antigen presentation defects paradoxically demonstrate enhanced responsiveness to PD-1 blockade, which we found is driven by enhanced antitumor immunity of gd T cells in this setting. These gd T cells represent a large fraction of all human T cells, but are yet veiled in mystery: their ways of activation are notoriously diverse and complex, they demonstrate key hallmarks of both innate and adaptive immunity, and, until date, have remained largely unstudied in the context of cancer immunotherapy. Our data demonstrates the clear potential of gd T cells in cancer immunotherapy to cover the blind spots of conventional CD8 T cell antitumor immunity.
In this project, we aim to develop novel immunotherapeutic strategies to further enhance antitumor immunity of gd T cells in MMR-d tumors. To do so, we will combine in vitro experimentation using cell lines and co-culture systems of tumor organoids and gd T cells, with bioinformatics approaches, and offer the opportunity to validate and translate these findings using our current clinical trials focused on MMR-d cancers. As we have recently discovered that specific signaling pathways are important for gd T cell immunity against MMR-d tumors, we will perform drug- and genetic screens to identify strategies to enhance stress signals expressed by tumor cells upon DNA-damage. Furthermore, we will explore the value of immunotherapeutic strategies to stabilize relevant ligands at the cell membrane of MMR-d cancers.
To lead this project, I am looking for a highly ambitious, creative and precise PhD student with a collaborative spirit and a strong background in immunology. You will be working in close collaboration with a highly multidisciplinary team, ranging from wet-lab biologists, to bioinformaticians, to clinicians. In our department of Molecular Oncology and Immunology, there are many opportunities to work together and get input from other leading laboratories in the field of cancer immunotherapy, including but not limited to the Peeper and Schumacher research groups.