Abstract

Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8+ cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms1,2. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers1. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms3,4. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells5,6. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent3,4 that is effective in aggressive prostate cancer7. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

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Acknowledgements

We thank L. Bastian, K. Wang, A. Umemura, M. K. Kim, M. Susani, E. Gurnhofer and F. Grizzi for discussions and research materials. Antibodies and MACS-beads were gifts from eBioscience, Biolegends and Miltenyi Biotec. Anti-PD-L1 and Pdl1/2−/− mice were from I. Mellman (Genentech). Research was supported by the National Institutes of Health (NIH) (CA127923 and AI043477), DFG and German Cancer Consortium (TR36, DKTK to G.W.), the Genome Research-Austria project ‘Inflammobiota’ (FWF and P26011 to L.K.), the CureSearch Foundation (to D.D.) and postdoctoral research fellowships from the German Research Foundation (DFG, SH721/1-1 to S.S.); Irvington-CRI (to S.S. and Z.Z.); CIRM (TG2-01154 to J.F.-B.) and FIRC/AIRC (to G.D.C.). M.K. is an ACS Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

Author information

Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, San Diego, California 92093, USA

    • Shabnam Shalapour
    • , Joan Font-Burgada
    • , Giuseppe Di Caro
    • , Zhenyu Zhong
    • , Elsa Sanchez-Lopez
    • , Debanjan Dhar
    • , Massimo Ammirante
    • , Amy Strasner
    •  & Michael Karin
  2. Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA

    • Shabnam Shalapour
    • , Joan Font-Burgada
    • , Giuseppe Di Caro
    • , Zhenyu Zhong
    • , Elsa Sanchez-Lopez
    • , Debanjan Dhar
    • , Massimo Ammirante
    • , Amy Strasner
    • , Donna E. Hansel
    •  & Michael Karin
  3. Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany

    • Gerald Willimsky
  4. Department of Surgery, Urology Division, University of California San Diego, 3855 Health Sciences Drive, San Diego, California 92093, USA

    • Christina Jamieson
    •  & Christopher J. Kane
  5. Department of Urology, Medical University of Vienna, 1090 Vienna, Austria

    • Tobias Klatte
  6. Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria

    • Peter Birner
    •  & Lukas Kenner
  7. Clinical Institute of Pathology, Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, 1210 Vienna, Austria

    • Lukas Kenner

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Contributions

M.K. and S.S. conceived and designed the project. S.S. performed experiments. S.S. and M.K. analysed data. J.F.B., Z.Z., D.D., M.A., G.W. and A.S. assisted with experiments and analysis. S.S., G.D.C., E.S.-L. and D.E.H. performed immunohistochemical analyses of human samples. G.W. performed Tag-specific ELISA. D.E.H., C.J., P.B., C.J.K., T.K. and L.K. collected and provided human specimens. M.K. and S.S. wrote the manuscript, with all authors contributing to writing and providing feedback.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael Karin.

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https://doi.org/10.1038/nature14395

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