Novel T cell biomarkers and the development of immunotherapeutic anti-tumor strategies

Abstract

The past decade has seen a rapid progress in identifying the complex tumor-immune interactions that occur in the tumor micro-environment (TME), on the basis of which response and prognostic biomarkers can be identified and novel immunotherapeutic anti-tumor strategies can be designed. Many of the recent breakthroughs in treatment of cancer are based on this increased understanding, with so-called checkpoint inhibition (i.e., removing the brake from immune cells) yielding long-term complete remissions in previously end-stage patients in many cancer types. Nevertheless, immunotherapy is not successful (yet) in all cancer types. For example, the five-year survival rate for one of the cancers studied in this thesis, epithelial ovarian cancer (EOC), only marginally increased from 32% in the 1990s to 38% at the moment. Furthermore, the past decades have seen increased incidences of many types of cancer in the Netherlands. Further exploration within the field of cancer immunology to identify immunotherapeutic targets and to develop new therapies is therefore warranted. This thesis is dedicated to these two goals and can be divided into several sections; 1) a section in which current literature on the implementation of Tumor Necrosis Factor receptor superfamily (TNFRSF) members in different immunotherapeutic strategies is reviewed, ranging from antibody- and ligand-based strategies to Chimeric Antigen Receptor (CAR)-T cell therapy, 2) a section focused on the identification of novel response and prognostic biomarkers expressed on peripheral blood lymphocytes (PBLs) and/or tumor infiltrating lymphocytes (TILs) and 3) a section in which the preclinical development of two novel immunotherapeutic anti-tumor strategies is presented.