Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer

• DOI: 10.1136/jitc-2021-003549
• Publication Date: 2022-01-12T16:46:21Z
• Authors: Francesco De Sanctis; Alessia Lamolinara; Federico Boschi; Chiara Musiu; Simone Caligola; Rosalinda Trovato; Alessandra Fiore; Cristina Frusteri; Cristina Anselmi; Ornella Poffe; Tiziana Cestari; Stefania Canè; Silvia Sartoris; Rosalba Giugno; Giulia Del Rosario; Barbara Zappacosta; Francesco Del Pizzo; Matteo Fassan; Erica Dugnani; Lorenzo Piemonti; Emanuela Bottani; Ilaria Decimo; Salvatore Paiella; Roberto Salvia; Rita Teresa Lawlor; Vincenzo Corbo; Youngkyu Park; David A Tuveson; Claudio Bassi; Aldo Scarpa; Manuela Iezzi; Stefano Ugel; Vincenzo Bronte
• Keywords: lymphocytes; 0301 basic medicine; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Basic Tumor Immunology; Adenocarcinoma; immunomodulation; adoptive; immunomodulation; immunotherapy; lymphocytes; tumor microenvironment; tumor-Infiltrating; adoptive; 3. Good health; 03 medical and health sciences; Nitrosative Stress; Tumor Microenvironment; tumor microenvironment; Humans; immunotherapy; Immunotherapy; RC254-282; tumor-Infiltrating; Carcinoma, Pancreatic Ductal; T-Lymphocytes, Cytotoxic

BackgroundPancreatic 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).MethodsWe 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.ResultsPDAC 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.ConclusionsTumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance.