Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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 MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44CD40 B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi 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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Primary PDA is responsive to PD-L1-targeted immunotherapy whereas liver metastases are resistant.
Fig. 2: Divergent immune landscape in primary versus metastatic PDA.
Fig. 3: T cells infiltrating PDA liver metastases are less immunogenic than in primary tumor.
Fig. 4: TAMs have reduced capacity for antigen presentation in metastatic PDA compared to primary tumor.
Fig. 5: Distinct B-cell profiles in primary and metastatic PDA.
Fig. 6: B cells corrupt innate and adaptive immunity in PDA liver metastases.
Fig. 7: Targeting B cells, CD200, or BTLA in PDA liver metastases enables efficacy for checkpoint-based immunotherapy.


  1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.

    CAS  Article  Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  Google Scholar 

  3. Chen J, Xiao-Zhong G, Qi XS. Clinical outcomes of specific immunotherapy in advanced pancreatic cancer: a systematic review and meta-analysis. J Immunol Res. 2017;2017:8282391.

    PubMed  PubMed Central  Google Scholar 

  4. Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med. 2017;23:556–67.

    CAS  Article  Google Scholar 

  5. Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 2016;532:245–9.

    CAS  Article  Google Scholar 

  6. Wang W, Marinis JM, Beal AM, Savadkar S, Wu Y, Khan M, et al. RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell. 2018;34:757–74.e7.

    CAS  Article  Google Scholar 

  7. Zhu Y, Herndon JM, Sojka DK, Kim KW, Knolhoff BL, Zuo C, et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity. 2017;47:597.

    CAS  Article  Google Scholar 

  8. Daley D, Zambirinis CP, Seifert L, Akkad N, Mohan N, Werba G, et al. gammadelta T cells support pancreatic oncogenesis by restraining alphabeta T cell activation. Cell. 2016;166:1485–99.e15.

    CAS  Article  Google Scholar 

  9. Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 2016;6:270–85.

    CAS  Article  Google Scholar 

  10. Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M, Koralov SB, et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 2016;6:247–55.

    CAS  Article  Google Scholar 

  11. Zhao Y, Shen M, Feng Y, He R, Xu X, Xie Y, et al. Regulatory B cells induced by pancreatic cancer cell-derived interleukin-18 promote immune tolerance via the PD-1/PD-L1 pathway. Oncotarget. 2018;9:14803–14.

    Article  Google Scholar 

  12. Enoksson SL, Grasset EK, Hagglof T, Mattsson N, Kaiser Y, Gabrielsson S, et al. The inflammatory cytokine IL-18 induces self-reactive innate antibody responses regulated by natural killer T cells. Proc Natl Acad Sci USA 2011;108:E1399–407.

    CAS  Article  Google Scholar 

  13. Canning C, O’Brien M, Hegarty J, O’Farrelly C. Liver immunity and tumour surveillance. Immunol Lett. 2006;107:83–8.

    CAS  Article  Google Scholar 

  14. Moini M, Schilsky ML, Tichy EM. Review on immunosuppression in liver transplantation. World J Hepatol. 2015;7:1355–68.

    Article  Google Scholar 

  15. Wrenshall LE, Ansite JD, Eckman PM, Heilman MJ, Stevens RB, Sutherland DE. Modulation of immune responses after portal venous injection of antigen. Transplantation. 2001;71:841–50.

    CAS  Article  Google Scholar 

  16. Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, et al. Autoimmune hepatitis. Nat Rev Dis Prim. 2018;4:18017.

    Article  Google Scholar 

  17. Disibio G, French SW. Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med. 2008;132:931–9.

    Article  Google Scholar 

  18. Yachida S, Iacobuzio-Donahue CA. The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med. 2009;133:413–22.

    Article  Google Scholar 

  19. Liu Y, Cao X. Immunosuppressive cells in tumor immune escape and metastasis. J Mol Med. 2016;94:509–22.

    Article  Google Scholar 

  20. Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell. 2016;30:668–81.

    CAS  Article  Google Scholar 

  21. Grunwald B, Harant V, Schaten S, Fruhschutz M, Spallek R, Hochst B, et al. Pancreatic premalignant lesions secrete tissue inhibitor of metalloproteinases-1, which activates hepatic stellate cells via CD63 signaling to create a premetastatic niche in the liver. Gastroenterology. 2016;151:1011–24.e7.

    Article  Google Scholar 

  22. Bodogai M, Moritoh K, Lee-Chang C, Hollander CM, Sherman-Baust CA, Wersto RP, et al. Immunosuppressive and prometastatic functions of myeloid-derived suppressive cells rely upon education from tumor-associated B cells. Cancer Res. 2015;75:3456–65.

    CAS  Article  Google Scholar 

  23. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.

    CAS  Article  Google Scholar 

  24. Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol. 2016;18:549–60.

    CAS  Article  Google Scholar 

  25. Lee JW, Stone ML, Porrett PM, Thomas SK, Komar CA, Li JH, et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature. 2019;567:249–52.

    CAS  Article  Google Scholar 

  26. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    CAS  Article  Google Scholar 

  27. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.

    CAS  Article  Google Scholar 

  28. Daley D, Mani VR, Mohan N, Akkad N, Pandian G, Savadkar S, et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J Exp Med. 2017;214:1711–24.

    CAS  Article  Google Scholar 

Download references


This work was supported by the American College of Surgeons Resident Research Fellowship (BD), Deutsche Forschungsgemeinschaft grant AY 126/1-1 (BA), and NIH grants CA168611 (DC, GM), CA203105 (GM), CA215471 (GM), CA19311 (GM), and DK106025 (GM).

Author information

Authors and Affiliations



BD and SA prepared the paper, performed in vivo and in vitro experiments and data analysis, and designed, supervised and interpreted the study; GSS, ML, BS, EL, MSS, AF, FY, CH, JG, AP, and YW performed in vitro experiments; JL, RC, RDS, MFC, CB, WW, SAAS, and GW performed in vivo experiments in addition to paper and figure preparation; BA and MK performed data analyis; DC contributed to critical review and paper writing; GM conceived, designed, supervised, analyzed and interpreted the study and provided critical review, and is senior author and corresponding author.

Corresponding author

Correspondence to George Miller.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Diskin, B., Adam, S., Soto, G.S. et al. BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer. Oncogene 41, 4349–4360 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links