This project focusses on the discovery and exploration of new immunotherapeutic targets against lymphoma. Currently, lymphomas are amongst the most curable forms of cancer, with treatment thus far usually based on chemotherapy and radiotherapy. An important problem that has remained, however, is that a sizeable number of patients develop refractory disease or cancer relapses. Therefore, our goal is to provide pre-clinical data to improve the treatment, to arrive at better long-term health of individuals who survived lymphoma. Immunotherapy is considered as viable alternative treatment, especially since lymphomas display numerous immune escape mechanisms.
To start, we will study the cell biology of lymphoma cells, focusing on a known mutation in the XPO1 gene that is observed in multiple classical Hodgkin Lymphoma (cHL) patients. cHL is characterized by HRS tumor cells that comprise 0.1-2.0% of the tumor microenvironment. In 25% of HL patients, HRS cells contain a mutation in the XPO1 gene (p.E571K), which encodes for a protein that mediates nucleocytoplasmic transport of RNA’s and proteins. Because this mutation alters the XPO1 interactome, a consequential shift in the composition of cytoplasmic proteins, XPO1E571K-specific neo-antigens might result in changes in peptide/MHC class I display to alert the immune system. We will explore how these tumor specific neo-antigens might act as target for therapeutic cellular or bispecific antibody-based immunotherapy, to offer long-lasting protective immunity against the tumor.
Niels van Heusden