Jlenia Guarnerio

Tumor cells constantly interact with the surrounding "normal" cells in the tumor microenvironment (TME), and these interactions are crucial for tumor growth and progression. Understanding this crosstalk is essential for developing novel therapies. We employ cutting-edge technologies such as single-cell RNA sequencing and spatial transcriptomics to analyze both mouse and human tissues. Additionally, we use functional genomics and immune-competent tumor mouse models to explore molecular mechanisms in context. Our research bridges basic science discoveries to clinical applications, aiming to create innovative cancer therapies that target tumor cells and reprogram the TME. Ongoing and Future Research Projects 1. Role of Cancer-Associated Fibroblasts (CAFs) in Tumor Growth and Immune Exclusion Tumors display heterogeneous environments, with varying levels of T cell infiltration impacting treatment responses, especially to immunotherapies. Our recent work identified glycolytic cancer-associated fibroblasts (glyCAFs) at T cell-excluded tumor margins, blocking T cell trafficking via the Cxcr6/Cxcl16 axis. Reprogramming glyCAFs or disrupting their interactions with T cells enhances tumor infiltration, improving control when combined with chemotherapy (Broz et al., Nature Communications 2024). Future research will investigate the mechanisms behind CAF accumulation in several tumor types and explore therapeutic CAF reprogramming to boost immune infiltration. 2. Circular RNAs as Mechanisms of Tumor Immune Exclusion Circular RNAs (circRNAs) are a unique class of stable non-coding RNAs formed by back-splicing. They can mimic viral dsRNAs, interacting with immune recognition proteins like RIG-I and PKR. Our studies revealed that specific circRNAs, such as circCsnk1g3, promote tumor growth by suppressing interferons and pro-inflammatory factors, hindering cytotoxic T cell functions (Piras and Ko, Nature Communications 2022). We will further explore circRNA-targeting and circRNA-engineering strategies as a therapeutic approach to enhance anti-tumor immune responses.