Deciphering the T cell Responses to Solid Tumors
T cells are a critical part of our body’s defense system. Importantly, T cells are key drivers in the efficacy of immunotherapies against cancer. We study T cell responses against Non-Small Cell Lung Cancer (NSCLC) and pediatric tumors, and we aim to bring Tumor-Infiltrating Lymphocyte (TIL) therapy for these tumors to the clinic. Together with our clinical partners at the Antoni van Leeuwenhoek hospital and the Princess Máxima Center, we have explored whether autologous TIL therapy (i.e. T cell expanded from tumor lesions and re-infused into the patients) is a viable option for solid tumors in adults and pediatric patients.
Our efforts have shown that the majority of TIL products from Non-Small-Cell Lung Cancer (NSCLC) patients contain variable but overall potent and tumor-reactive T cells. This research line has resulted in the setup of a clinical trial for NSCLC tumors that will begin soon.
Furthermore, we uncovered that TIL therapy can be an option for pediatric tumors, despite of their low mutational burden. Importantly, the anti-tumoral responses of TIL products from pediatric tumors are primarily driven by non-classical T cells, a finding we are currently exploring further with the aim to offer optimized TIL products for pediatric patients in the future.
Regulation of protein expression in T cells
To drive the rapid onset of T cell responses against target cells, their protein production must be swiftly reorganized and geared towards the production of cytotoxic molecules. Likewise, this re-organization of gene expression is key to drive T cell differentiation into different subsets.
Whereas RNA expression analysis has taught us how T cells are programmed towards specific gene expression, this RNA profile only informs us what a cell is capable of, not which proteins are actually produced. In fact, RNA levels are overall a poor proxy for the actual protein levels within cells. We therefore study the molecular mechanisms that define the protein production in T cells, with a specific focus on the role of post-transcriptional events driven by RNA-binding proteins (RBPs).
Using molecular biology and immunological approaches, we uncovered how and which RBPs fine-tune T cell responses. We have recently defined the RBP landscape in human T cells, both from an RNA-centric and RBP-centric approach, and we study how the RBP-RNA interactions alter upon T cell activation. Furthermore, we are exploring whether RBP deletions can be exploited to boost anti-tumoral immune responses.
Our fundamental studies on RNA translation regulation directly feed into recent efforts to uncover the protein landscape of tumor-infiltrating T cells. To further decipher the rules that define gene expression, we developed machine learning pipelines to identify sequence determinants defining the RNA and protein abundance in human T cells. Unravelling these fundamental rules for protein expression could possibly be exploited for improving T cell responses against cancer.
Wolkers Group members
Text by Monika Wolkers.
This article was created for Cancer Center Amsterdam.