Complement Inhibition in the Immunotherapy of Breast Cancer
Abstract
The role of complement in cancer metastasis has not yet been recognized. In addition, a role of adaptive immunity in distant from primary tumor sites in preventing metastasis is unclear. Utilizing a model of breast cancer, we found that the complement anaphylatoxin C5a receptor (C5aR) facilitated lung and liver metastasis by suppressing effector CD8+ and CD4+ T cell responses. Mechanisms of this suppression involved recruitment of immature myeloid cells to distant sites and regulation of TGF- and IL-10 production in these cells. TGF- and IL-10 favored generation of Regulatory T (Treg) cells and Th2 predominant responses that rendered CD8+ T cells dysfunctional. Importantly, pharmacological blockade of C5aR or its genetic ablation in C5aR-deficient mice reduced metastases. Depletion of CD8+ T cells abolished this beneficial effect suggesting that CD8+ T cells are responsible for C5aR inhibition-dependent reduction in metastasis. In contrast to previous findings, C5aR-signaling appeared to promote Treg cell generation and suppress T cell responses in metastases-targeted organs. These findings indicate that immunomodulatory functions of C5aR are highly context dependent. Furthermore, these data open a new avenue for developing complement-based immunotherapies to prevent or reduce cancer metastasis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2014
- Accession Number
- ADA600563
Entities
People
- Maciej Markiewski
Organizations
- Texas Tech University Health Sciences Center