Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response

• Published in: Journal of Immunology Vol. 179; no. 2; pp. 977 - 983
• Main Authors: Sinha, Pratima, Clements, Virginia K, Bunt, Stephanie K, Albelda, Steven M, Ostrand-Rosenberg, Suzanne
• Format: Journal Article
• Language: English
• Published: United States 15.07.2007
• Subjects: Animals; Coculture Techniques; Flow Cytometry; Interleukin-10 - biosynthesis; Interleukin-12 - biosynthesis; Lymphocyte Activation - immunology; Macrophages - immunology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Myeloid Cells - immunology; Neoplasms, Experimental - immunology; Receptor Cross-Talk - immunology; T-Lymphocytes, Regulatory - immunology; Tumor Escape - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.2.977

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.