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Dougan, Stephanie K.
Cancer research (Chicago, Ill.), 12/2019, Letnik: 79, Številka: 24_SupplementJournal Article
Abstract Like virally infected cells, tumors can evade CD8 T-cell recognition by downregulation of MHC class I. Loss of MHC class I and IFNg sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. The cellular (c)-IAPs regulate classical and alternative NF-kB signaling, and induction of noncanonical NF-kB signaling using IAP antagonists mimics costimulatory signaling, augmenting antitumor immunity. We now show that induction of noncanonical NF-kB signaling promotes antitumor immunity across a range of orthotopic and spontaneous pancreatic cancer models, and induces T cell-dependent immune responses even in b2m-/- tumors, demonstrating that direct CD8 T-cell recognition of tumor cell expressed MHC class I is not required. Here we show that MHC class I negative tumors can be controlled in a T-cell dependent fashion by repolarized intratumoral phagocytes. In wild-type mice, but not mice incapable of mounting antigen-specific T cell responses, treatment with IAP antagonists increases phagocytosis of tumor cells, as determined by flow cytometry, imaging flow cytometry, and quantitative immunofluorescence. This mechanism of action inspired combination therapy with CD47 blockade, a strategy that induced curative responses in otherwise refractory preclinical models. To our knowledge, this is the first example of antigen specific immunotherapy for tumors that are refractory to checkpoint blockade due to loss of MHC class I or IFNg sensing. Citation Format: Stephanie K. Dougan. Tumor-specific T cells reprogram mononuclear phagocytes for destruction of checkpoint blockade-resistant pancreatic cancer abstract. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I09.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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