Targeting NSCLC With Adoptive DNT Cell Transfer In Combination With Anti-PD1 Blockade

Back ground:Lung cancer is one of the leading causes of cancer mortality worldwide.Recent years,immune checkpoint blockade against PD-1 has shown success in the treatment of lung cancer,but not all patients respond.DNT cell has been shown can target leukemia in vitro and in xenograft models without induce allogeneic reactivity,which make it become a potential cell product against cancer.But their role in lung cancer is not clear.Here we explore whether DNT cell naturally infiltrate in human lung cancer and the role of human DNT cells in targeting established lung cancer either alone or in combination with Nivolumab(anti-PD-1 antibody)and describe underlying mechanisms.Methods:To understand the infiltration and characters of DNT cells in human lung cancer,DNT from resected lung cancer tissues of patients were isolated and stained with antibodies and analyzed by flow cytometry.DNT cell enriched and expanded from healthy donor and lung cancer patient's peripheral blood was using to compare their expansion capacity and anti-tumor function.Lung cancer xenograft models were developed to determine the anti-tumor effect of DNT cells alone or in combination with anti-PD-1 antibody.To explore the underlying mechanisms,tumorinfiltrating DNT cells was quantified by histology and characterized by flow cytometry.Results:With flow cytometry analysis of DNT from lung cancer patient,we demonstrated tumor infiltrating lymphocytes contained a lower frequency of DNT cells with a higher expression of PD-1 relative to normal lung tissue.Through ex vivo expanded patient-and healthy donor-derived DNT cells,we observed they shown similar cytotoxicity against lung cancer cells in vitro,but patient derived DNT present a lower yield.We further revealed DNT cells can significantly inhibited the growth of established lung cancer xenografts,which was further augmented by antiPD-1 through increased DNT cell tumor accumulation and maintained their cytotoxicity function.Conclusion:This study supports the use of DNT cells for adoptive cellular therapy against lung cancer either alone or in combination with anti-PD-1.