TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression

Abstract

Transforming growth factor beta (TGF-beta) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-beta remain unclear. TGF-beta exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-beta enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-beta regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-beta regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-beta antagonists and biomarkers for patient selection and efficacy of TGF-beta antagonist treatment.

Figure 1

The TGF-β ligands signal through the type I and type II TGF-β receptors. Canonical signaling proceeds with phosphorylation of SMAD2 and SMAD3, which then combine with SMAD4 to enter the nucleus and mediate growth inhibition. TGF-β binding to its receptors activates many non-canonical signaling pathways, including small GTPases (RhoA, PKN, and Rock), p38 kinase and PI3 kinase pathways. These pathways are important in regulating tumor-cell migration and metastasis. In addition, bone morphogenetic proteins (BMPs) signal through SMAD1, SMAD5 or SMAD8, which form complexes with SMAD4, which activate or repress targeted gene transcription that is important for tissue and organ development. Smad 6 and 7 are negative mediators in the TGF-β signaling pathway.

Figure 2

TGF-β switches from tumor suppressor in the premalignant stages of tumorigenesis to tumor promotion in later stages of the disease leading to metastasis. Progression to metastatic disease is generally accompanied by decreased or altered TGF-β responsiveness and increased expression or activation of the TGF-β ligand. When combined with genetic or epigenetic perturbations in tumor cells, along with alteration in the tumor microenvironment, the spectrum of biological responses to TGF-β are altered. EMT: epithelial mesenchymal transition (Figure modified from Ref. 32)

Figure 3

TGF-β affects multiple components of the immune system. TGF-β inhibits the function of natural killer (NK) and CD8+ CTL (cytotoxic T lymphocytes), blocking the ‘cytotoxic program’ key proteins such as perforin, granzymes and cytotoxins. TGF-β induces Treg and Th17 cell differentiation and inhibits B-cell proliferation and IgA secretion. In addition, TGF-β inhibits dendritic function, block type I macrophage and neutrophil development but promotes type II macrophages and neutrophils, and mediates the immune suppression function of MISCs.

Figure 4

TGF-β regulation of tumor microenvironment. (a) Cellular players in tumor microenvironment. (b) The mechanisms by which TGFβ signaling switches from a tumor suppressor to a tumor promoter are shown. TGFβ signals through the type II receptor mediate growth inhibition of carcinoma cells. When TβRII is deleted or downregulated, the result is increased chemokine/chemokine-receptor signaling, such as CXCL1–CXCL5/CXCR2 and SDF-1–CXCR4. Host-derived immature myeloid Gr-1+CD11b+ cells are recruited into the tumor microenvironment through these chemokine mechanisms. These Gr-1+CD11b+ cells express high level of MMPs and TGFβ1, which promote tumor invasion and immune suppression. The effect of Gr-1+CD11b+ cells on the tumor microenvironment and host immune surveillance constitute a tumor-promoting mechanism of TGFβ signaling.