例如:"lncRNA", "apoptosis", "WRKY"

B cell-Derived IL35 Drives STAT3-Dependent CD8+ T-cell Exclusion in Pancreatic Cancer.

Cancer Immunol Res. 2020 Mar;8(3):292-308. Epub 2020 Feb 05
Bhalchandra Mirlekar 1 , Daniel Michaud 2 , Samuel J Lee 1 , Nancy P Kren 1 , Cameron Harris 1 , Kevin Greene 3 , Emily C Goldman 4 , Gaorav P Gupta 4 , Ryan C Fields 5 , William G Hawkins 5 , David G DeNardo 6 , Naim U Rashid 7 , Jen Jen Yeh 8 , Autumn J McRee 9 , Benjamin G Vincent 10 , Dario A A Vignali 11 , Yuliya Pylayeva-Gupta 12
Bhalchandra Mirlekar 1 , Daniel Michaud 2 , Samuel J Lee 1 , Nancy P Kren 1 , Cameron Harris 1 , Kevin Greene 3 , Emily C Goldman 4 , Gaorav P Gupta 4 , Ryan C Fields 5 , William G Hawkins 5 , David G DeNardo 6 , Naim U Rashid 7 , Jen Jen Yeh 8 , Autumn J McRee 9 , Benjamin G Vincent 10 , Dario A A Vignali 11 , Yuliya Pylayeva-Gupta 12
+ et al

[No authors listed]

Author information
  • 1 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 2 Department of Cell Biology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 3 Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 4 Department of Radiation Oncology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 5 Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
  • 6 Department of Medicine, Barnes-Jewish Hospital and the Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
  • 7 Department of Biostatistics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 8 Department of Surgery, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 9 Department of Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 10 Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
  • 11 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 12 Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.

摘要


Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of duanyu18133 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of duanyu18133 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.