Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression

TLDR

Chronic inflammation is linked to cancer development and progression, and myeloid‑derived suppressor cells that inhibit T‑cell activation are frequently found in patients. The study aimed to investigate how IL‑1β‑driven inflammation promotes tumor growth by creating a chronic inflammatory microenvironment in 4T1 mammary carcinoma. Researchers transfected 4T1 tumors with IL‑1β to induce a sustained inflammatory milieu and examined resulting immune changes. IL‑1β‑transfected tumors shortened survival, elevated splenic immature Gr1⁺CD11b⁺ MDSCs that lack IL‑1R, persisted after tumor removal, and were independent of adaptive or innate lymphocytes, indicating that IL‑1β enhances immune suppression and tumor progression via MDSC induction.

Abstract

Abstract Epidemiological and experimental observations support the hypothesis that chronic inflammation contributes to cancer development and progression; however, the mechanisms underlying the relationship between inflammation and cancer are poorly understood. To study these mechanisms, we have transfected the mouse 4T1 mammary carcinoma with the proinflammatory cytokine IL-1β to produce a chronic inflammatory microenvironment at the tumor site. Mice with 4T1/IL-1β tumors have a decreased survival time and elevated levels of immature splenic Gr1+CD11b+ myeloid-derived cells. These myeloid suppressor cells (MSC) are present in many patients with cancer and inhibit the activation of CD4+ and CD8+ T lymphocytes. 4T1/IL-1β-induced MSC do not express the IL-1R, suggesting that the cytokine does not directly activate MSC. Neither T or B cells nor NKT cells are involved in the IL-1β-induced increase of MSC because RAG2−/− mice and nude mice with 4T1/IL-1β tumors also have elevated MSC levels. MSC levels remain elevated in mice inoculated with 4T1/IL-1β even after the primary tumor is surgically removed, indicating that the IL-1β effect is long lived. Collectively, these findings suggest that inflammation promotes malignancy via proinflammatory cytokines, such as IL-1β, which enhance immune suppression through the induction of MSC, thereby counteracting immune surveillance and allowing the outgrowth and proliferation of malignant cells.