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Cryptic transcripts: the masked heroes that break tumor immunotolerance and rescue the immunotherapy response

Boek - Dissertatie

In the last years, immunotherapy revolutionized cancer treatment in terms of quality of life and life years saved. Immune-checkpoint blockage (ICB) therapy, like anti-programmed death-1 (anti-PD-1) therapy, blocks the inhibitory interaction between immune-checkpoint ligands on the tumor and their receptors on T-cells (or vice versa). Despite the ground-breaking clinical success, ICB therapy responses are variable and unpredictable, while resistance, relapse and side-effects often occur. As societal, financial and emotional burdens are increasing, the need for a conclusive and clinically-applicable predictive biomarker becomes more and more clear. Tumor-intrinsic characteristics like tumor immunogenicity play a key role, while the influence of the tumor micro-environment (TME) cannot be ignored. Therefore, I aim to evaluate both tumor-intrinsic traits, like tumor immunogenicity, and changes in the TME to unravel the mechanism underlying immunotherapy response in (hypoxic) tumors and to combat resistance. Previously, we already showed that DNA methylation repels binding of the hypoxia-inducible factors (HIFs), the main transcription factors executing the hypoxic response. Interestingly, we observed that, upon pharmacological demethylation, many new HIF binding sites were enriched at repetitive elements like cryptic transcripts (CTs), which extend well beyond the known retrotransposons. Interestingly, these retrotransposons have been associated with tumor immunogenicity, immune activation and ICB response. As such, hypoxia-induced CTs have the potential to break tumor immunotolerance (the tolerance of the immune system towards the tumor) and improve ICB responses specifically in hypoxic tumors. In this PhD thesis, I thus studied whether and how these CTs increase tumor immunogenicity, activate the immune system and ameliorate the response to ICB therapy. I focused specifically on hypoxic tumors at first, but also verified our results as a general principle. The fine-grained resolution of single-cell technologies moreover allowed me to distinguish CT expression in cancer versus stromal cells while complementary evaluating the role of the TME, specifically dendritic cells, in this ICB response.
Jaar van publicatie:2021
Embargoed until:19/05/2023