Li et al. show that the intratumoral natural killer T (NKT) cells established an immunologically active tumor microenvironment and enhanced antitumor immunity in pancreatic ductal adenocarcinoma (PDA). Interactions between CD40L on NKT cells and CD40 on myeloid cells induced type I IFN production in myeloid cells, but not in NKT cells, initiating adaptive antitumor responses and intratumoral immune cell infiltration. Administration of folinic acid to PDA tumor-bearing mice increased NKT cells in the TME and improved their response to anti-PD-1 treatment in an NKT cell- and type I IFN signaling-dependent manner.
Contributed by Shishir Pant
ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.
Author Info: (1) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. (2) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. Graduate Program in
Author Info: (1) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. (2) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794. Medical Scientist Training Program, Stony Brook University Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794. (3) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065.
