Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors. RPS19 also induces the production of immunosuppressive cytokines, including TGF-β, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes. RPS19 promotes generation of regulatory T cells while reducing infiltration of CD8+ T cells into tumors. Reducing RPS19 in tumor cells or blocking the C5a receptor 1–RPS19 interaction decreases RPS19-mediated immunosuppression, impairs tumor growth, and delays the development of tumors in a transgenic model of breast cancer. This work provides initial preclinical evidence for targeting RPS19 for anticancer therapy enhancing antitumor T cell responses.
This work was supported by grants from the Australian National Health and Medical Research Council (456060 and 1027369) and Australian Research Council (DP150104609, DP160104442, and CE140100011) (to D.P.F.), Cancer Prevention and Research Institute of Texas Grant RP 120168 and Department of Defense Tuberous Sclerosis Research Program Grant TS 140010 (to M.K.), and National Institutes of Health Grant 1R01CA190209 (to M.M.M.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- Alexa Fluor
- C5a receptor 1
- C5aR1 antagonist
- dendritic cell
- myeloid-derived suppressor cell
- MHC class II
- ribosomal protein S19
- short hairpin RNA
- tumor-draining lymph node
- regulatory T cell.
- Received December 7, 2016.
- Accepted January 27, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.