Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response

TLDR

Although the immune system can protect against cancer, many patients are immunosuppressed, partly because elevated myeloid‑derived suppressor cells block CD4+ and CD8+ T‑cell activation. In 4T1 mouse mammary carcinoma, MDSC–macrophage cross‑talk suppresses tumor immunity by increasing IL‑10 and decreasing IL‑12 through cell‑contact, and gemcitabine partially reverses this effect by reducing MDSC, preserving IL‑12, and preventing IL‑10 elevation, thereby promoting T‑cell activation and tumor rejection in IL‑4Rα−/− mice.

Abstract

Abstract 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-4Rα−/− 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.