Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients
- 357 Downloads
Multiple factors in the tumor microenvironment were found to inhibit antitumor adaptive immune responses, allowing tumor persistence and growth. In this study, ascites from ovarian cancer patients were collected. We observed that a population of interleukin-10+ B (IL-10+ B) cells was preferentially enriched in the ascites. This population was associated with naive B cell phenotype or IgM or class-switched memory B cell phenotypes. The frequencies of IL-10+ B cells were negatively correlated with the frequencies of interferon gamma-producing (IFN-g+) CD8+ T cells and were positively correlated with the frequencies of Foxp3+ CD4+ T cells. To examine whether increased IL-10+ B cells in ascites could directly result in increased suppression of IFN-g production by CD8+ T cells, we cocultured CD8+ T cells with autologous blood B cells or ascitic B cells and found that CD8+ T cells cocultured with ascitic B cells demonstrated significantly suppressed IFN-g production. This suppression was in part mediated by IL-10 as well as low CD80/CD86 expression, since depletion of IL-10 and stimulation of CD28 partially reverted IL-10+ B cell-mediated suppression. Together, these data demonstrated an additional regulatory mechanism in the tumor microenvironment, which utilizes IL-10+ B cells.
KeywordsB cell Ovarian cancer
This work was supported by Shandong Provincial Medical and Health Science Technology Development Project (2014WS0011) and Jinan Science Technology Development Project (2014–34).
Conflicts of interest
- 5.Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116. Available from: http://stm.sciencemag.org/content/5/200/200ra116.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved; Available from: http://dx.doi.org/10.1038/nature14011.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25:214–21. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3636159&tool=pmcentrez&rendertype=abstract.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61. Elsevier. Available from: http://www.cell.com/article/S1074761314002301/fulltext.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Nelson BH. The impact of T-cell immunity on ovarian cancer outcomes. Immunol Rev. 2008;222:101–16. Available from: http://onlinelibrary.wiley.com.ezproxy.library.uvic.ca/doi/10.1111/j.1600-065X.2008.00614.x/abstract.CrossRefPubMedGoogle Scholar
- 15.Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32:129–40. Available from: http://www.hubmed.org/display.cgi?uids=20079667.CrossRefPubMedGoogle Scholar
- 17.Sayi A, Kohler E, Toller IM, Flavell RA, Müller W, Roers A, et al. TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J Immunol. 2011;186:878–90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21149607.CrossRefPubMedGoogle Scholar
- 21.Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R, Wejksza K, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 2011;71:3505–15. Available from: http://cancerres.aacrjournals.org/content/71/10/3505.full.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Siewe B, Stapleton JT, Martinson J, Keshavarzian A, Kazmi N, Demarais PM, et al. Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8+ T cell function in vitro. J Leukoc Biol. 2013;93:811–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23434518.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Geffroy-Luseau A, Chiron D, Descamps G, Jégo G, Amiot M, Pellat-Deceunynck C. TLR9 ligand induces the generation of CD20+ plasmablasts and plasma cells from CD27+ memory B-cells. Front Immunol. 2011;2:83. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2011.00083/abstract.CrossRefPubMedPubMedCentralGoogle Scholar