Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

• 成果类型: Article
• 署名作者: Li, Jiayun; Moresco, Philip; Fearon, Douglas T.
• 署名单位: Cold Spring Harbor Laboratory; State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Stony Brook University Hospital; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12094
• DOI: 10.1073/pnas.2403917121
• 发表日期: 2024-07-16
• 关键词: killer t-cells; dendritic cells; i interferon; cutting edge; innate; activation; cd40; responses; antibody; vivo

摘要

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.