Project Funding Details

The Tumor Immune Microenvironment (TIME) composition and organization of immune cells in tertiary lymphoid structures (TLS) holds promise for advancing outcome predictions and assessing responses to immune checkpoint blockade (ICB) in solid tumors. The actin regulatory protein hMENA has been recently identified as a key node in integrin adhesome, cellular architecture control and gene expression regulation. We have demonstrated that its isoforms, hMENA11a and hMENAΔv6, play roles in epithelial-mesenchymal plasticity and impacts on communication among tumor cells, extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), T and B cells. We proposed that hMENA in tumor cells and CAFs could affect TLS presence, localization and clinical outcomes in early-stage (N0) NSCLC patients and ICB response in different solid tumors. The driving hypothesis is that the different pattern of hMENA isoform expression in NSCLC influences ECM composition, mechano-signaling, gene expression and secretory pathways in tumor cells and CAFs. This, in turn may have a key role in TLS formation, and immunopermissive or immunosuppressive TIME. Studying this new hypothesis will open up a novel research direction to modulate hMENA-related molecular and cellular components linked to dysfunctional TLS, paving the way for novel TIME-tailored effective ICB treatment in NSCLC patients. - Uncovering cellular and molecular mechanisms underlying the composition of TIME affected by hMENA isoform pattern of expression in cancer cells and CAFs with a focus on: TGFβ, ECM and the TLS-organizer lymphotoxin beta receptor (LTβR). - Exploring the role of hMENA isoforms in tumor tissues and their impact on TLS-enriched TIME and immune cells in periphery, NSCLC patient prognosis, ICB response. - Identifying drugs to inhibit hMENA isoform expression in cancer cells and CAFs, by leveraging organotypic tissue slices. We will explore the role of hMENA isoform expression in ECM architecture, TGFβ signaling/secretion, chromatin regulation of LTβR as organizer of TLS-related TIME. The mechano-signaling and gene regulation will be evaluated in tumor cells and CAFs. Spatial transcriptomic deconvolution of TIME, with a focus on TLS, in early-stage N0 NSCLC patients naïve of treatment will be performed. The development of a murine model will validate the role of hMENA isoforms in TLS composition and maintenance. The integration of spatial distribution of TLS with T and B cells at single cell level will be explored in ICB-treated patients. Organotypic tissue slices will be used to test drugs capable of modulating hMENA isoforms and TLS composition. We envision that the detailed hMENA-related TLS organization and signatures have potential far-reaching impact in identifying programs shaping pro- or anti- immunogenic TIME. We expect to gather a comprehensive view of the TIME and peripheral immune-profiling of N0 NSCLC patients. The integration of spatial and single-cell transcriptomics may identify potential biomarkers of ICB response in both TIME and blood. Finally, we expect to identify drugs inhibiting hMENA isoforms in cancer cells and CAFs modulating TIME. We posit that the integrated results of our project may have a direct impact in understanding mechanisms of immune-evasion and may contribute to enhance ICB therapy effectiveness in NSCLC.