The immune system is essential for maintaining the health and homeostasis of our body. This defense system not only combats invading pathogens and cancerous cells, but also repairs and maintains tissue integrity. These critical functions require an intricate fine-tuning of gene expression in immune cells, so that their activity is rapid but tightly regulated. The Wolkers research team at Sanquin is investigating how T cells react to solid tumors, with a special emphasis on understanding how the precise control of protein expression governs T cell responses against these tumors.

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.

Attend the CCAll meeting on Friday November 17, from 9 to 10 am. Location: Amsterdam UMC – Vumc, PK 1Y 141, De Boelelaan 1117, 1081 HV Amsterdam, or email Center Amsterdam for a Teams link to attend online.

For more information, contact Monika Wolkers at Sanquin, or read more about her research by visiting the Sanquin and Oncode Institute (link 1), (link 2) websites.

Wolkers Group members

Branka Popovic

Kaspar Bresser

Koos Rooijers

Nandhini Kanagasabesan

Antonia Bradaric

Leyma Wardak

Nordin Zandhuis

Anouk Jurgens

Valeria Lattanzio

Suzanne Castenmiller

Zan Hozjan

Monika Wolkers

Text by Monika Wolkers.

This article was created for Cancer Center Amsterdam.

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