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

Published

Journal Article

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.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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • September 2016

Published In

Volume / Issue

  • 6 / 9

Start / End Page

  • 1022 - 1035

PubMed ID

  • 27297552

Pubmed Central ID

  • 27297552

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

International Standard Serial Number (ISSN)

  • 2159-8274

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-15-1412

Language

  • eng