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Cancer Discov. 2016 Sep;6(9):1022-35. doi: 10.1158/2159-8290.CD-15-1412. Epub 2016 Jun 13.

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

Author information

1
Department of Immunology, Duke University Medical Center, Durham, North Carolina.
2
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
3
Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Chaoyang District, Beijing, China.
4
Hepatopancreatobiliary Surgery Department, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
5
Thoracic Surgery Department, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
6
Department of Radiology, Duke University Medical Center, Durham, North Carolina.
7
Department of Radiology, Duke University Medical Center, Durham, North Carolina. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
8
Department of Immunology, Duke University Medical Center, Durham, North Carolina. youwen.he@duke.edu.

Abstract

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.

PMID:
27297552
PMCID:
PMC5010476
DOI:
10.1158/2159-8290.CD-15-1412
[Indexed for MEDLINE]
Free PMC Article

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