Complement Activation via a C3a Receptor Pathway Alters CD4+ T Lymphocytes and Mediates Lung Cancer Progression

被引：104

作者：

Kwak, Jeff W. ^{[1
]}

Laskowski, Jennifer ^{[1
]}

Li, Howard Y. ^{[1
,2
]}

McSharry, Maria V. ^{[1
]}

Sippel, Trisha R. ^{[1
]}

Bullock, Bonnie L. ^{[1
]}

Johnson, Amber M. ^{[1
]}

Poczobutt, Joanna M. ^{[1
]}

Neuwelt, Alexander J. ^{[1
]}

Malkoski, Stephen P. ^{[1
]}

Weiser-Evans, Mary C. ^{[1
,3
]}

Lambris, John D. ^{[1
,4
]}

Clambey, Eric T. ^{[5
]}

Thurman, Joshua M. ^{[1
]}

Nemenoff, Raphael A. ^{[1
,3
]}

机构：

[1] Univ Colorado Denver, Dept Med, Box C281,12700 East 19th Ave, Aurora, CO 80045 USA

[2] Vet Affairs Med Ctr, Denver, CO USA

[3] Univ Colorado Denver, Dept Pharmacol, Aurora, CO 80045 USA

[4] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[5] Univ Colorado Denver, Dept Anesthesiol, Aurora, CO 80045 USA

来源：

CANCER RESEARCH | 2018年 / 78卷 / 01期

关键词：

ANTITUMOR IMMUNITY; CELL RESPONSES; TUMOR; MICROENVIRONMENT; THERAPY; SYSTEM; C5A; HOMEOSTASIS; METASTASIS; MODULATION;

D O I：

10.1158/0008-5472.CAN-17-0240

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The complement cascade is a part of the innate immune system that acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3(-/-) mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFN gamma(+)/TNF alpha(+)/IL10(+) CD4(+) and CD8(+) T cells. Immunodepletion of CD4(+) but not CD8(+) T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway. (C) 2017 AACR.

引用

页码：143 / 156

页数：14