De Sanctis, Francesco, Lamolinara, Alessia, Boschi, Federico, Musiu, Chiara, Caligola, Simone, Trovato, Rosalinda, Fiore, Alessandra, Frusteri, Cristina, Anselmi, Cristina, Poffe, Ornella, Cestari, Tiziana, Canè, Stefania, Sartoris, Silvia, Giugno, Rosalba, Del Rosario, Giulia, Zappacosta, Barbara, Del Pizzo, Francesco, Fassan, Matteo, Dugnani, Erica, Piemonti, Lorenzo, Bottani, Emanuela, Decimo, Ilaria, Paiella, Salvatore, Salvia, Roberto, Lawlor, Rita Teresa, Corbo, Vincenzo, Park, Youngkyu, Tuveson, David A, Bassi, Claudio, Scarpa, Aldo, Iezzi, Manuela, Ugel, Stefano, Bronte, Vincenzo (January 2022) Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer. Journal for ImmunoTherapy of Cancer, 10 (1). e003549-e003549. ISSN 2051-1426
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Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment of cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit the success of immunotherapy as a single agent, thereby suggesting the need for the development of a multitargeted approach. The goal is to foster T lymphocyte infiltration within the tumor landscape and neutralize cancer-triggered immune suppression, to enhance the therapeutic effectiveness of immune-based treatments, such as anticancer adoptive cell therapy (ACT). METHODS: We examined the contribution of immunosuppressive myeloid cells expressing arginase 1 and nitric oxide synthase 2 in building up a reactive nitrogen species (RNS)-dependent chemical barrier and shaping the PDAC immune landscape. We examined the impact of pharmacological RNS interference on overcoming the recruitment and immunosuppressive activity of tumor-expanded myeloid cells, which render pancreatic cancers resistant to immunotherapy. RESULTS: PDAC progression is marked by a stepwise infiltration of myeloid cells, which enforces a highly immunosuppressive microenvironment through the uncontrolled metabolism of L-arginine by arginase 1 and inducible nitric oxide synthase activity, resulting in the production of large amounts of reactive oxygen and nitrogen species. The extensive accumulation of myeloid suppressing cells and nitrated tyrosines (nitrotyrosine, N-Ty) establishes an RNS-dependent chemical barrier that impairs tumor infiltration by T lymphocytes and restricts the efficacy of adoptive immunotherapy. A pharmacological treatment with AT38 ([3-(aminocarbonyl)furoxan-4-yl]methyl salicylate) reprograms the tumor microenvironment from protumoral to antitumoral, which supports T lymphocyte entrance within the tumor core and aids the efficacy of ACT with telomerase-specific cytotoxic T lymphocytes. CONCLUSIONS: Tumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance.
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