Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy
Open accessAbstract
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 mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. 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 cells. 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 agent that is effective in aggressive prostate cancer. 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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Regulatory B cells can suppress antitumor immunity via the secretion of immunosuppressive cytokines, such as IL-10 and TGF-β, and the induction of Tregs.
“Among various subtypes, regulatory B cells can suppress antitumor immunity via the secretion of immunosuppressive cytokines, such as IL-10 and TGF-β, and the induction of Tregs [42, 43].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [42]
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- Authors
- Shalapour, S., Font-Burgada, J., Di Caro, G., Zhong, Z., Sanchez-Lopez, E., Dhar, D., Willimsky, G., Ammirante, M., Strasner, A., Hansel, D. E., Jamieson, C., Kane, C. J., Klatte, T., Birner, P., Kenner, L., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Medical University of Vienna (AT)
- University of Veterinary Medicine Vienna (AT)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Nature
- Published
- 2015-04-29
- Volume
- 521
- Issue
- 7550
- Pages
- 94-98
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4501632
- OpenAlex
- W1980313076
- Cited by
- 611
- References
- 60
- Citations by year
- 2026: 47 · 2025: 55 · 2024: 62 · 2023: 58 · 2022: 69 · 2021: 82 · 2020: 52 · 2019: 57 · 2018: 38 · 2017: 38 · 2016: 36 · 2015: 16
- FWCI
- 18.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (CA127923, R01CA127923)
- National Institute of Allergy and Infectious Diseases (AI-043477, R01AI043477, R37AI043477)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- oxaliplatin, immunogenic chemotherapy, castration-resistant prostate cancer, TGF-beta, PD-L1, IL-10, cytotoxic T lymphocytes, immunogenic cell death, chemoresistance, B cells, tumor microenvironment, tumor-associated B cells, tumour-associated macrophages, tumor-associated neutrophils
- MeSH terms
- Oxaliplatin, Animals, Antibodies, Neoplasm, Antineoplastic Agents, Cells, Cultured, Humans, Immunoglobulin A, Lymphocyte Activation, Male, Mice, Inbred C57BL, Organoplatinum Compounds, Plasma Cells, Prostatic Neoplasms, T-Lymphocytes, Cytotoxic, Neoplastic Stem Cells, Signal Transduction, Transforming Growth Factor beta, Interleukin-10, Receptors, Transforming Growth Factor beta, Adoptive Transfer, Mice, I-kappa B Kinase, Chemokine CXCL13, B7-H1 Antigen
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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