Modulation of the antitumor immune response by complement

Maciej MM., et al. 2008. Nat immunol. 11, 1225-1235

Speaker: Wen-Hsin Yao (姚文欣)                                  Time: 13:00~14:00, Nov. 26, 2008

Commentator: Dr. Neng-Yao Shih (施能耀博士)           Place: Room 601

Abstract:

The role of complement system in the anti-tumor immune response is under discussion recently, especially under the discussions that formation of membrane attack complex or blocking the complement regulatory protein may enhance immunetherapies efficacy (1). However, during the activation of complement system, other soluble effector proteins are also produced, such as C3a and C5a anaphylatoxins. Since inflammation may also positively affect tumor growth, what the authors want to know is whether those effector proteins contribute to tumor development. In this paper, the author use TC-1, an advanced mouse cervical cancer cell, as model. After subcutaneous injection of TC-1 on wild type mice, the C3 cleavage product were found extensively deposited along tumor vasculature; besides, the growth of tumor is impaired in C3-defecient (C3^d) mice, these results suggest that complement activation are involved in tumor growth. Since C5a activate several cellular responses that involved in tumor growth (2), the effect of C5a on TC-1 tumor had been assessed. Results showed that either blocking C5aR by antagonist (C5aRa) or using C5aR^d mice, the growth of tumor was impaired. However, C5a seems not to directly induce tumor growth. Given that the cytotoxic T cell have a crucial function in controlling tumor growth, it had been found that with C5aRa treatment, tumor was heavily infiltrated by CD8⁺ T cell; additionally, by usingα-CD8 in C5aR^d mice, it shown that tumor growth was promoted. A C5aR-bearing cells that suppress the anti-tumor CD⁺8 T cell immune response by secreting ROS and RNS, called Myeloid- derived suppressor cells (MDSC), may be the mediator. Compared with C5aR^d tumor-bearing mice, the ratio of PMN-MDSC to MO-MDSC in tumor is larger in wild type mice; in addition, MDSC in tumor of wild type mice contain larger amount of ROS and RNS probably due to slightly larger amount of arginase-1 expression, furthermore, they can inhibit T cell proliferation in vitro. In conclusion, C5asuppress the CD8⁺T cell anti-tumor function and tumor-infiltration by recruiting MDSC migration to TC-1 tumor and regulate its ability of producing ROS and RNS, and these findings may open a new window for cancer immunotherapy.

Reference

1.      Macor P, Tedesco F. Complement as effector system in cancer immunotherapy Immunol Lett. 111(1):6-13 (2007)

2.      Monk PN, Scola AM, Madala P, Fairlie DP. Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol. 152(4):429-48 (2007)