Current cancer immunotherapies are effective only in ~40-60% of the cases. One of the main reasons behind such inefficiency is the escape of cancer cells from host immune surveillance (immune evasion) by epigenetic de-regulation of immune response genes. The aim of the Laboratory is to decipher the mechanisms of repression and activation of immune response genes in cancer cells and use them to develop new types of immunotherapies.

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Our primary focus is the regulation of Interferon-stimulated genes (ISGs). ISGs are abundant (~10% of human coding genome) and tightly regulated immune response genes whose expression is activated by cytokines – interferons. ISGs are crucial for controlling inflammation and signalling between infected or cancer-transformed cells and host immune system. ISGs’ expression triggers pathogen clearance and recognition of tumours by immune system. Due to their crucial role in limiting cancer proliferation, epigenetic repression of ISGs is one of the main mechanisms behind immune evasion and cancer evolution. This phenomenon opens two exciting research prospects – scientific and clinical.

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On the scientific side, we found out that activation and repression of ISGs is regulated by a complex network of factors. Notably, changes in their expression state are associated with dynamic remodelling of chromatin (i.e., differential balance between active and repressive chromatin modifications), genome architecture (i.e., loops between enhancer/silencers and promoters) and alternative transcription (i.e., regulated expression from multiple transcriptional start sites). Furthermore, we revealed that selected ISGs are subjects of transcriptional memory – their activation can be memorized post-stimulus even in continuously proliferating cells and allow faster/higher activation upon stimulus re-challenge. How all these factors cooperate in gene regulation, what codes transcriptional memory and what underlies switches between active-repressive expression state remains unknown. The Lab aims to address these knowledge gaps and use ISGs as a paradigm for regulation of gene expression and epigenetic inheritance of active chromatin state - two aspects of molecular biology with incomplete understanding and fundamental importance.

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On the clinical side, ISG-mediated immune evasion, despite widespread occurrence, remains largely unaddressed by current clinical cancer treatments. Current immunotherapies largely do not directly modulate ISGs’ expression in cancer cells and do not restore ISGs-dependent immune surveillance. Through work on fundamental principles behind ISG regulation, our applied long-term aim is the development of first-in-class immunotherapy centered at modulation of ISGs’ expression. We are aware that truly innovative research takes time (e.g. current checkpoint immunotherapies are built on decades of fundamental research), but we will capitalize on our research and entrepreneurship experience to build practical solutions to the disease.