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Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.

Publication ,  Journal Article
Wang, Y; Sun, S-N; Liu, Q; Yu, Y-Y; Guo, J; Wang, K; Xing, B-C; Zheng, Q-F; Campa, MJ; Patz, EF; Li, S-Y; He, Y-W
Published in: Cancer Discov
September 2016

UNLABELLED: In contrast to its inhibitory effects on many cells, IL10 activates CD8(+) tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell- and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8(+) TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. SIGNIFICANCE: Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti-PD-1 to enhance anti-PD-1 efficacy; a targeted IL10 delivery to CD8(+) TILs using anti-PD-1-IL10 or anti-CTLA4-IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022-35. ©2016 AACR.See related commentary by Peng et al., p. 953This article is highlighted in the In This Issue feature, p. 932.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

September 2016

Volume

6

Issue

9

Start / End Page

1022 / 1035

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • T-Lymphocytes
  • Signal Transduction
  • Programmed Cell Death 1 Receptor
  • Neoplasms
  • Mice, Knockout
  • Mice
  • Lymphocytes, Tumor-Infiltrating
  • Interleukin-10
  • Immunomodulation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, Y., Sun, S.-N., Liu, Q., Yu, Y.-Y., Guo, J., Wang, K., … He, Y.-W. (2016). Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression. Cancer Discov, 6(9), 1022–1035. https://doi.org/10.1158/2159-8290.CD-15-1412
Wang, Yu, Sheng-Nan Sun, Qing Liu, Yang-Yang Yu, Jian Guo, Kun Wang, Bao-Cai Xing, et al. “Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.Cancer Discov 6, no. 9 (September 2016): 1022–35. https://doi.org/10.1158/2159-8290.CD-15-1412.
Wang Y, Sun S-N, Liu Q, Yu Y-Y, Guo J, Wang K, et al. Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression. Cancer Discov. 2016 Sep;6(9):1022–35.
Wang, Yu, et al. “Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.Cancer Discov, vol. 6, no. 9, Sept. 2016, pp. 1022–35. Pubmed, doi:10.1158/2159-8290.CD-15-1412.
Wang Y, Sun S-N, Liu Q, Yu Y-Y, Guo J, Wang K, Xing B-C, Zheng Q-F, Campa MJ, Patz EF, Li S-Y, He Y-W. Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression. Cancer Discov. 2016 Sep;6(9):1022–1035.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

September 2016

Volume

6

Issue

9

Start / End Page

1022 / 1035

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • T-Lymphocytes
  • Signal Transduction
  • Programmed Cell Death 1 Receptor
  • Neoplasms
  • Mice, Knockout
  • Mice
  • Lymphocytes, Tumor-Infiltrating
  • Interleukin-10
  • Immunomodulation