Details

Autor(en) / Beteiligte

• Diskin, Brian
• Adam, Salma
• Soto, Gustavo Sanchez
• Liria, Miguel
• Aykut, Berk
• Sundberg, Belen
• Li, Eric
• Leinwand, Joshua
• Chen, Ruonan
• Kim, Mirhee
• Salas, Ruben D
• Cassini, Marcelo F
• Buttar, Chandan
• Wang, Wei
• Farooq, Mohammad Saad
• Shadaloey, Sorin A A
• Werba, Gregor
• Fnu, Amreek
• Yang, Fan
• Hirsch, Carolina
• Glinski, John
• Panjwani, Angilee
• Weitzner, Yael
• Cohen, Deirdre
• Asghar, Usman
• Miller, George

Titel

BTLA + CD200 + B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Ist Teil von

• Oncogene, 2022-09, Vol.41 (38), p.4349-4360

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCII IL10 macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24 CD44 CD40 B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1 IL18 tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.