| Title | Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression |
| Authors | Wang, Yu Sun, Sheng-Nan Liu, Qing Yu, Yang-Yang Guo, Jian Wang, Kun Xing, Bao-Cai Zheng, Qing-Feng Campa, Michael J. Patz, Edward F., Jr. Li, Shi-You He, You-Wen |
| Affiliation | Duke Univ, Med Ctr, Dept Immunol, Durham, NC USA. Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing, Peoples R China. Beijing Univ Chinese Med, Sch Chinese Mat Med, Key Lab TCM Informat Engineer, State Adm TCM, Beijing, Peoples R China. Peking Univ, Key Lab Carcinogenesis & Translat Res, Beijing Canc Hosp & Inst, Hepatopancreatobiliary Surg Dept,Minist Educ,Sch, Beijing, Peoples R China. Peking Univ, Beijing Canc Hosp & Inst, Thorac Surg Dept, Sch Oncol, Beijing, Peoples R China. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. Duke Univ, Med Ctr, 207 Res Dr,330 Jones Bldg, Durham, NC 27710 USA. |
| Keywords | INTERLEUKIN-10-DEFICIENT MICE CYTOKINE PRODUCTION C3A RECEPTOR C5A RECEPTOR IL-10 CANCER LYMPHOCYTES EXPRESSION RESPONSES MICROENVIRONMENT |
| Issue Date | 2016 |
| Publisher | CANCER DISCOVERY |
| Citation | CANCER DISCOVERY.2016,6(9),1022-1035. |
| 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. (C) 2016 AACR. |
| URI | http://hdl.handle.net/20.500.11897/433353 |
| ISSN | 2159-8274 |
| DOI | 10.1158/2159-8290.CD-15-1412 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 北京肿瘤医院 |
