Transforming Growth Factor-β Signaling in Immunity and Cancer

Abstract

Transforming growth factor (TGF)-β is a crucial enforcer of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Perturbations in TGF-β signaling underlie inflammatory diseases and promote tumor emergence. TGF-β is also central to immune suppression within the tumor microenvironment, and recent studies have revealed roles in tumor immune evasion and poor responses to cancer immunotherapy. Here, we present an overview of the complex biology of the TGF-β family and its context-dependent nature. Then, focusing on cancer, we discuss the roles of TGF-β signaling in distinct immune cell types and how this knowledge is being leveraged to unleash the immune system against the tumor.

Figure 1.. Key players in TGF-β suppression of tumor adaptive immunity.

Several prevalent cancer types exhibit a TGF-β-rich TME. TGF-β is produced by cancer cells and by several other cell types present in the TME including Tregs. Fibroblasts, macrophages and platelets are also main TGF-β producers in tumors (not shown). Elevated TGF-β-levels block naïve T cell differentiation towards a Th1 effector phenotype, promotes their conversion towards the Treg subset and dampens antigen presenting functions of dendritic cells.

Figure 2.. The TGF-β signaling pathway.

(A) Synthesis and release of active TGF-β (adapted from (Kelly et al., 2017)). In the endoplasmic reticulum, each pro-TGF-β molecule is assembled into a dimer via three interchain disulfide bonds. Following cleavage by the endoprotease Furin, the C-terminal fragment remains non-covalently associated with the disulfide-linked LAP homodimer. This molecule is termed the small latent complex. Three main mechanisms of release of active TGF-β are represented: (i) Extracellular protease cleavage of LAP domain. (ii) Tethering of small latent complex to extracellular matrix through LTBP1 and release of active TGF-beta by integrin-transmitted tension upon cell contraction. (iii) Tethering of small latent complex to GARP on the cell surface and release of active TGF-beta by integrins. (B) Signal transduction by TGF-β. The fundamental steps of ligand-induced formation of a paired-kinase receptor complex, and receptor-mediated phosphorylation of R-SMAD proteins for the formation of a trimeric receptor complex are shown. The accessory receptor proteoglycan Betaglycan (BG) presents TGF-β to the signaling receptors. In the nucleus, the activated SMAD heterotrimeric complex binds to target cis-regulatory sites as determined by interactions with lineage-determining transcription factors (LDTFs) and other signal-driven transcription factors (SDTFs). CDK8 and CDK9 phophorylate SMADs in this complex for further activation and eventual degradation. SMAD phosphatases (not shown) reverse these phosphorylation, and PARP-mediated parylation causes SMAD dissociation from DNA. The inhibitory SMAD7 recruits SMURF ubiquitin ligases to target the receptor for degradation, whereas ubiquitin specific peptidases USP11 and USP15 counterbalance this process.

Figure 3.. Tumor suppressor and promoting functions of TGF-β signaling. Left.

In homeostasis, TGF-β signals regulate key processes in multiple tissues including their growth, regeneration and identity. In the immune system, TGF-β instructs tolerance and suppresses inflammation. This function is particularly relevant in the gastrointestinal tract. Center. Genetic alterations can modify the output of TGF-β signals in tumor initiating cells. During the initial stages of carcinogenesis, TGF-β operates as main tumor suppressor by imposing cytostatic and apoptotic programs in tumor cells. A proinflammatory environment fosters the onset of cancer. Loss of TGF-β signals in the microenvironment contributes to exacerbate inflammation in this context. Secretion of pro-survival factors and cytokines by stromal and immune cells pushes continuous regeneration in a harsh inflammatory environment, which eventually leads to the onset of cancer. Right. During tumor progression, selective pressure promotes loss of the cytostatic and tumor suppressor function of TGF-beta in cancer cells. In general, this process occurs via two distinct mechanisms. Acquisition of loss of function mutations in TGF-beta pathway components renders tumor cells resistant to TGF-β thus enabling growth in a TGF-β-rich environment present in many advanced cancers. Alternatively, TGF-beta signals are reinterpreted in cancer cells to instruct tumor-promoting functions such as the ability to migrate and colonize foreign organs. In the TME of several prevalent tumor types, TGF-β operates as central mechanism of immune evasion.

Figure 4.. Immune evasion mediated by TGF-β signaling in late stage cancers.

The central circle depicts phenotypic transitions instructed by TGF-beta in the distinct immune cell types present in the TME as described in the text. The outer part summarizes the key processes regulated by TGF-beta signaling in immune cells. We depict direct transcriptional responses driven SMADs, in some cases in cooperation with cell specific transcription factors.