Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche.

Surya Kumari Vadrevu,Priya Sharma,Sasikanth Manne,Othon Almanza,Navin K Chintala,Linley Riediger,Wojciech Gorczyca,Clayton Cleveland,Magdalena Karbowniczek,Sharad K Sharma,Maciej M Markiewski,David P Fairlie

doi:10.1158/0008-5472.can-14-0157

Abstract

The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGFβ and IL10 production in these cells. TGFβ and IL10 favored generation of T regulatory cells (Treg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. Depletion of CD8(+) T cells abolished this beneficial effect, suggesting that CD8(+) T cells were responsible for the effects of C5aR inhibition. In contrast to previous findings, we observed that C5aR signaling promoted Treg generation and suppressed T-cell responses in organs where metastases arose. Overall, our findings indicated that the immunomodulatory functions of C5aR are highly context dependent. Furthermore, they offered proof-of-concept for complement-based immunotherapies to prevent or reduce cancer metastasis.

Highlights

Preventing cancer metastasis is a Holy Grail of cancer therapy, as the majority of cancer deaths are attributed to this process [1]
We found that C5a receptor (C5aR) deficiency reduced lung (Fig. 1A and B) and liver (Supplementary Fig. S1A and S1B) metastatic burden without significantly affecting the growth of primary breast tumors (Fig. 1C) in a syngeneic model of breast cancer (4T1), which closely mimics stage IV of human breast cancer [16]
Decreased metastatic burden together with the lack of an impact of C5aR deficiency on primary tumor growth suggests that C5aR promotes metastasis through mechanisms independent of those operating in primary tumors

Summary

Introduction

Preventing cancer metastasis is a Holy Grail of cancer therapy, as the majority of cancer deaths are attributed to this process [1] Progress in this area has been limited by our poor understanding of its mechanism. Recent evidence has indicated that, in addition to the mechanisms operating in neoplastic cells [2], alterations in host homeostasis, in the immune system, contribute to metastasis [3]. These alterations occur in the primary tumor microenvironment [2], roles for host-derived cells and mediators at sites distal to the tumor have been reported [4].

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Results

Conclusion