Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response.
Although the immune system has the potential to protect against malignancies, many individuals with cancer are immunosuppressed. Myeloid-derived suppressor cells (MDSC) are elevated in many patients and animals with tumors, and contribute to immune suppression by blocking CD4(+) and CD8(+) T cell activation. Using the spontaneously metastatic 4T1 mouse mammary carcinoma, we now demonstrate that cross-talk between MDSC and macrophages further subverts tumor immunity by increasing MDSC production of IL-10, and by decreasing macrophage production of IL-12. Cross-talk between MDSC and macrophages requires cell-cell contact, and the IL-12 decrease is dependent on MDSC production of IL-10. Treatment with the chemotherapeutic drug gemcitabine, which reduces MDSC, promotes rejection of established metastatic disease in IL-4Ralpha(-/-) mice that produce M1 macrophages by allowing T cell activation, by maintaining macrophage production of IL-12, and by preventing increased production of IL-10. Therefore, MDSC impair tumor immunity by suppressing T cell activation and by interacting with macrophages to increase IL-10 and decrease IL-12 production, thereby promoting a tumor-promoting type 2 response, a process that can be partially reversed by gemcitabine.
Sinha
Pratima
P
Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
Clements
Virginia K
VK
Bunt
Stephanie K
SK
Albelda
Steven M
SM
Ostrand-Rosenberg
Suzanne
S
D000818:Animals; D018920:Coculture Techniques; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D020239:Receptor Cross-Talk / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
D016753:Interleukin-10; D018664:Interleukin-12