UOSD IMMUNOLOGY AND IMMUNOTHERAPY
Head: Dr. Paola Nisticò, MD
PI Nisticò: The group activity obtained results on the role that the isoforms of the actin regulator hMENA may have in shaping NSCLC microenvironment by regulating the dialogue among tumor, fibroblasts and immune cells. We have demonstrated that hMENA and its isoforms contributes to cancer progression by regulating tumor cell-autonomous signalling, including:
1) AXL; TGFβ/SMAD and IFN type I pathways with PD-L1 up-regulation related to the absence of hMENA11a isoform. In parallel, hMENA/hMENADv6 isoforms identify a subtype of pro-invasive immunosuppressive CAFs. hMENA isoforms from both tumor cells and CAFs impact ECM composition and quality and localization of immune cell in the tumor site. Studies are ongoing to evaluate hMENA derived signatures as theranostic biomarker in NSCLC patients treated with immune checkpoint inhibitors. We have identified significant modulation of immune cell subsets in periphery with respect to distal and tumoral tissue in NSCLC patients by multicolour flow cytometry. An in depth immune-monitoring in prostate cancer patients undergoing curative radiotherapy RT revealed important modification of immune cell frequency and quality, indicating the role of novel targets to be used in combined radio/immunotherapeutic clinical trials.
Paola Nisticò as National coordinator of the WG Immunotherapy of Alleanza Contro il Cancro contributes through an integrated experimental and clinical work in different network projects.
PI Di Modugno: To explore the mechanisms that underline the role of hMENA isoforms in the dialogue among tumor cells CAFs and immune cells we found that the pattern of hMENA isoforms expression in NSCLC tumor cells and CAFs affects the expression level and the activation of the downstream NF-kB pathways of the lymphotoxin beta receptor, crucial in tertiary lymphoid structures organization and maintenance. In CAFs hMENA affects the FN1 expression and fibrillogenesis, a relevant process in extracellular matrix assembly that could act as a barrier to the lymphocyte infiltration in the tumor. Multiplex staining of NSCLC tissue with confocal microscopy evidenced the TLS peritumoral localization in the presence of an hMENA enriched stroma.
To evaluate the role of irradiation (IR) on CAF secretoma we treated lymphocytes with the CAF conditioned medium, demonstrating that IR potentiates the immunosuppressive properties of CAFs and inhibits the lymphocyte proliferation.
PI Cardone: We have identified key metabolic vulnerabilities supporting metastases in a model of metastatic Triple-negative breast cancer and highlighted the importance of lipid metabolism in metastatic cancer stem-like cells survival. To identify novel potential therapeutic to treat a specific subpopulation of patients with pancreatic cancer we have demonstrated that Decitabine may represent an anticancer drug repurposing opportunity.
PI Mileo: To delve into the molecular mechanisms elicited by the remodelling of actin cytoskeleton and involved in cancer progression we identified a pivotal role of HPV16E7-GSN physical interaction on Epithelial-Mesenchymal Transition via Hippo-YAP axis.
As part of the integrated analysis of bidirectional crosstalk between tumor cell and stromal compartment and, specifically, of the role of cytoskeletal dynamics on lung cancer progression, we evaluated also the CAF pro-tumor activity related to cytoskeletal features actin-dependent, driven also by hMena isoforms activity. By exploring the signaling pathways involved in the “cooperative dialogue” between tumor cells and their supporting microenvironment components, we focused our studies on the paracrine activity of CAFs on cellular mechanotransduction processes and on YAP-dependent gene induction related to NSCLC cancer progression. We attempted to characterize the hMena-related CAF functionality via the identification of CAF pro-tumorigenic soluble factors able to affect on lung cancer cells the Hippo/YAP axis, a pivotal signaling pathway involved on tumor progression, stemness, metastasis and immune evasion.
PI Sistigu: We showed that Type I IFNs (IFNs-I), during immunogenic chemotherapy, may act as molecular hubs of resistance as they trigger the epigenetic regulator KDM1B, which account for an adaptive, yet reversible, transcriptional rewiring on cancer cells towards stemness and immune escape. Indeed, pharmacological inhibition of KDM1B, antagonizes CSC appearance. IFN-I-adapted CSCs show phenotypical/functional heterogeneity in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Importantly, in breast cancer patients receiving anthracycline-based chemotherapy, IFN-I and KDM1B signatures positively correlate with CSC and immune evasion markers. By elucidating the downside of IFNs-I, our findings may ultimately help the development of more informed, combined therapies to increase the chances of cure.
PI Toietta: We aim to develop innovative therapeutic strategies for targeting TME components. To this end, we have identified TME-related genes as putative targets for chimeric antigen receptor-modified T cells (CAR-T) and bispecific T-cell engagers (BiTE). Moreover, we are assessing whether treatment with oncolytic viruses can promote T cell trafficking into “cold” solid tumors. Moreover, we characterized a clinical grade product obtained by emulsification of adipose tissue-derived stromal vascular fraction, used in regenerative medicine clinical studies in virtue of its immunosuppressive, immunomodulatory, and pro-angiogenic potentials.
PI Venuti: In cooperation with the HPV Unit we participate in programs of cancer prevention on HPV vaccination for males and, recently, we started an International clinical trial on this issue as Italian Coordinator Centre. Patients were enrolled and three years follow-up taking place. We achieved new insight the therapy of HPV-associated cancer. The study in collaboration with University of California, identified a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV16 E5 oncoprotein, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. Exploring the role of HPV in non-genital cancers, we evidenced that presence of persistent infection by beta papillomavirus type 15 might influence the biological fate of patient with a rare hereditary disease, Inontinentia Pigmenti (IP) by altering NF-κB activation and apoptosis in IKKγ mutated cells, favouring their survival and possibly the development of tumors in the late stage of disease. The platform for the production of DNA therapeutic vaccines has been improved by exploring adjuvating activity of natural compounds. Finally, our mouse model of oral cancer AT-84 was challenged with oncolytic viruses to improve CAR –T cell therapy in solid tumours.