Complementing Cancer Metastasis

Complement is an effector of innate immunity and a bridge connecting innate immunity and subsequent adaptive immune responses. It is essential for protection against infections and for orchestrating inflammatory responses. Recent studies have also demonstrated contribution of the complement system to several homeostatic processes that are traditionally not considered to be involved in immunity. Thus, complement regulates homeostasis and immunity. However, dysregulation of this system contributes to several pathologies including inflammatory and autoimmune diseases. Unexpectedly, studies of the last decade have also revealed that complement promotes cancer progression. Since the initial discovery of tumor promoting role of complement, numerous preclinical and clinical studies demonstrated contribution of several complement components to regulation of tumor growth through their direct interactions with the corresponding receptors on tumor cells or through suppression of antitumor immunity. Most of this work, however, focused on a role of complement in regulating growth of primary tumors. Only recently, a few studies showed that complement promotes cancer metastasis through its contribution to epithelial-to-mesenchymal transition and the premetastatic niche. This latter work has shown that complement activation and generation of complement effectors including C5a occur in organs that are target for metastasis prior to arrival of the very first tumor cells. C5a through its interactions with C5a receptor 1 inhibits antitumor immunity by activating and recruiting immunosuppressive cells from the bone marrow to the premetastatic niche and by regulating function and self-renewal of pulmonary tissue-resident alveolar macrophages. These new advancements provide additional evidence for multifaceted functions of complement in cancer

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

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 TGF beta and IL10 production in these cells. TGF beta and IL10 favored generation of T regulatory cells (T-reg) 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 T-reg 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. (C) 2014 AACR

The Role of Complement in Angiogenesis

The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer. Interestingly, complement-dependent mechanisms involved in angiogenesis are very much context dependent, including anti- and proangiogenic functions. Here, we discuss these new developments that place complement among other important regulators of homeostatic and pathological angiogenesis, and we provide the perspective on how these newly discovered complement functions can be targeted for therapy

Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells

A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone

The role of complement in tumors

Activation of the complement system is one of the earliest responses to invading pathogens and tissue damage (1). Complement activation leads to production of a range of effectors including the opsonin C3b, the anaphylatoxins C3a and C5a, and the C5b-9 complex (membrane attack complex; MAC) (2, 3). In addition to potent innate immune activities, complement effector systems also contribute to efficient adaptive immune responses (4). While critical to proper immune function, inappropriate or excessive complement activation contributes to many pathological inflammatory conditions (5), including cancer. As described in this issue, the complement system is increasingly recognized as a double-edged sword: on the one hand contributing to the anti-tumor response, but on the other protecting the tumor against immune attack and promoting metastasis

The role of complement in tumors

Activation of the complement system is one of the earliest responses to invading pathogens and tissue damage (1). Complement activation leads to production of a range of effectors including the opsonin C3b, the anaphylatoxins C3a and C5a, and the C5b-9 complex (membrane attack complex; MAC) (2, 3). In addition to potent innate immune activities, complement effector systems also contribute to efficient adaptive immune responses (4). While critical to proper immune function, inappropriate or excessive complement activation contributes to many pathological inflammatory conditions (5), including cancer. As described in this issue, the complement system is increasingly recognized as a double-edged sword: on the one hand contributing to the anti-tumor response, but on the other protecting the tumor against immune attack and promoting metastasis