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682 Antibody-mediated blockade of interleukin-10 receptor-alpha promotes the activation of immune cells from in vitro dissociated tumor samples
  1. Alexey Berezhnoy,
  2. Kalpana Shah,
  3. Daorong Liu,
  4. Peter Lung,
  5. Vatana Long,
  6. Kurt Stahl,
  7. Douglas Smith,
  8. Francine Chen,
  9. Hua Li,
  10. Jonathan Li,
  11. Ralph Alderson,
  12. Valentina Ciccarone,
  13. James Tamura,
  14. Ezio Bonvini,
  15. Gundo Diedrich and
  16. Paul Moore
  1. MacrGenics, Inc., Rockville, MD, USA


Background Interleukin-10 (IL-10) is a multifunctional cytokine that can mediate immune suppression or activation depending on the immunological context. Mouse studies have demonstrated that blockade of IL-10 enhances immune response against tumors and chronic viral infections;1 2 intriguingly, high concentrations of long-acting, pegylated IL-10 have also shown anti-tumor activity.3 Here we investigated IL-10 and IL-10 receptor-alpha (IL-10RA) expression profiles in normal and tumor tissues as well as the immunological effects of modulating the IL-10 pathway via antibody-mediated blockade of IL-10RA.

Methods IL-10 and IL-10RA mRNA are expressed by several tumors, including renal, lung, breast, and colon cancers. Fluorescent in-situ hybridization revealed that the majority of IL-10RA was expressed by CD3-negative tumor-infiltrating cells, localized in close proximity to T cells in the tumor microenvironment (TME). Immunohistochemistry studies confirmed expression of IL-10RA in the TME, while no expression was detected in healthy tissues. Furthermore, dissociated tumor cells produced biologically active levels of IL-10 in culture.

Results Monoclonal antibodies (mAbs) against IL-10RA prevented IL-10 signaling and enhanced release of IL-12 by monocyte-derived dendritic cells activated with suboptimal LPS concentrations. The effect of IL-10RA blockade was greater than that observed with IL-10 neutralizing mAbs. In mixed lymphocyte reactions and superantigen-driven T-cell activation, IL-10RA blockade enhanced IL-2 secretion by T lymphocytes. Consistent with earlier observations in mouse models,4 the effect of IL-10RA blockade was nonredundant with blockade of the PD-1/PD-L1 axis, resulting in enhanced IL-2 and interferon-gamma secretion by T cells when both pathways were inhibited. Blockade of IL-10RA during CD3-redirected in vitro killing of tumor cells by PBMC induced IL-12 release as well as upregulation of CD86 and HLA-DR by CD3-negative cells. In in vitro dissociated tumor cells, IL-10RA blockade induced release of IL-2, interferon-gamma and other proinflammatory cytokines; additional PD-1/PD-L1 axis blockade further enhanced cytokine release.

Conclusions In summary, antibody-mediated IL-10RA blockade can potentiate immune activation in the dissociated tumor cells and may be a valuable addition to cancer immunotherapies, including redirected T-cell killing and checkpoint blockade.


  1. Vicari A, et al. J. Exp. Med 2002;196:541–549.

  2. Ejrnaes M, et al. J Exp Med 2006;203:2461–72.

  3. Emmerich J, et al. Cancer Res 2012. 72:3570–3581.

  4. Brooks D, et al. Proc Natl Acad Sci U S A 2008;105:20428–33.

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