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We previously showed that ICB selects for pancreatic tumor cells that are defective in IFN-\u03b3\u2013inducible MHC-I, prompting us to test the impact of IL-15 complex (IL-15C) in overcoming ICB resistance. Here, we show that IL-15C markedly expands circulating NK cells, CD8+ T cells, and CD4+Cxcr3+ T cells in an orthotopic pancreatic ductal adenocarcinoma (PDA) animal model. In tumors, IL-15C\u2009+\u2009anti-PD-L1 increased CD8+ T-cell effector cytokine production and interfered with T-cell exhaustion, including mitigating IL-10. In NK cells, IL-15C\u2009+\u2009anti-PD-L1 modulated NK cell IFN-\u03b3 production but did not alter Nkg2d, Nkg2a, Klrg1, IL-10, or granzyme B. IL-15C\u2009+\u2009anti-PD-L1 significantly prolonged animal survival, leading to tumor eradication in a subset of animals, whereas monotherapies only transiently prolonged survival. Therapeutic benefit was dependent on CD8+ T cells and independent of NK cells and Nkg2d. Together, our study supports that IL-15C improves anti-PD-L1 in PDA through sustaining antitumor T-cell function.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf314","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:42:06Z","timestamp":1763534526000},"page":"3228-3237","source":"Crossref","is-referenced-by-count":4,"title":["IL-15 complex enhances therapeutic efficacy of anti-PD-L1 in a T cell\u2013dependent and NK cell\u2013independent manner in a murine model of pancreatic ductal adenocarcinoma"],"prefix":"10.1093","volume":"214","author":[{"given":"Adam L","family":"Burrack","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Center for Immunology, University of Minnesota, University of Minnesota , Minneapolis, MN,","place":["United 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States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe C","family":"Schmiechen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Center for Immunology, University of Minnesota, University of Minnesota , Minneapolis, MN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Center for Immunology, University of Minnesota, University of Minnesota , Minneapolis, MN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6931-226X","authenticated-orcid":false,"given":"Kristina S","family":"Burrack","sequence":"additional","affiliation":[{"name":"Center for Immunology, University of Minnesota, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Department of Medicine, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Division of Infectious Disease, Hennepin Healthcare Research Institute , Minneapolis, MN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingunn M","family":"Stromnes","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Center for Immunology, University of Minnesota, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Masonic Cancer Center, University of Minnesota , Minneapolis, MN,","place":["United States"]},{"name":"Center for Genome Engineering, University of Minnesota , Minneapolis, 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