Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.
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.
Department of Immunology, Duke University Medical Center, Durham, North Carolina.
Yu
Y
Wang
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
Sheng-Nan
SN
Sun
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
Qing
Q
Liu
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.
Yang-Yang
YY
Yu
Department of Immunology, Duke University Medical Center, Durham, North Carolina.
Jian
J
Guo
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.
Kun
K
Wang
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.
Bao-Cai
BC
Xing
Thoracic Surgery Department, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
Qing-Feng
QF
Zheng
Department of Radiology, Duke University Medical Center, Durham, North Carolina.
Michael J
MJ
Campa
Department of Radiology, Duke University Medical Center, Durham, North Carolina. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
Edward F
EF
Patz
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
Shi-You
SY
Li
Department of Immunology, Duke University Medical Center, Durham, North Carolina. youwen.he@duke.edu.
You-Wen
YW
He
D000818:Animals; D019898:Autocrine Communication; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016000:Cluster Analysis; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D003176:Complement C3; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D003165:Complement System Proteins