Exploiting the STAT3 Nexus in Cancer-Associated Fibroblasts to Improve Cancer Therapy

Abstract

The tumor microenvironment (TME) is composed of a heterogenous population of cells that exist alongside the extracellular matrix and soluble components. These components can shape an environment that is conducive to tumor growth and metastatic spread. It is well-established that stromal cancer-associated fibroblasts (CAFs) in the TME play a pivotal role in creating and maintaining a growth-permissive environment for tumor cells. A growing body of work has uncovered that tumor cells recruit and educate CAFs to remodel the TME, however, the mechanisms by which this occurs remain incompletely understood. Recent studies suggest that the signal transducer and activator of transcription 3 (STAT3) is a key transcription factor that regulates the function of CAFs, and their crosstalk with tumor and immune cells within the TME. CAF-intrinsic STAT3 activity within the TME correlates with tumor progression, immune suppression and eventually the establishment of metastases. In this review, we will focus on the roles of STAT3 in regulating CAF function and their crosstalk with other cells constituting the TME and discuss the utility of targeting STAT3 within the TME for therapeutic benefit.

Keywords: STAT (signal transducer and activator of transcription); cancer associated fibroblasts (CAF); cytokines; tumor development; tumor microenvironment.

Figure 1

Canonical and non-canonical STAT3 signaling. Binding of ligands such as cytokines and growth factors to their cognate receptors stimulate receptor dimerization and recruitment of Janus kinase (JAK). JAK phosphorylates the cytoplasmic tails of the receptor to create a docking site for STAT3. In the canonical pathway, STAT3 is phosphorylated at the Tyr⁷⁰⁵ residue and form homodimers or STAT3:STAT1 heterodimers that modulate gene expression in the nucleus. Maximal transcriptional activation can also be induced by the non-canonical activation of STAT3 via phosphorylation at the Ser⁷²⁷ residue. p-Ser⁷²⁷ STAT3 can then translocate to the mitochondria to regulate the electron transport chain (ETC) and production of reactive oxygen species (ROS).

Figure 2

Intrinsic effects of STAT3 signaling in CAFs. Cytokines such as IL-6, IL-11 and IL-17 mediate the phosphorylation and activaton of STAT3 resulting in the transformation of normal fibroblasts into cancer associated fibroblasts (CAFs). Activated CAFs can then remodel the extracellular matrix, promote matrix cross-linking leading to stromal stiffness and mechanical stress. Mechanical stresses in the stroma consequently leads to the collapse of blood vessels and induction of hypoxia which creates an environment permissible to tumor development. CAFs can also promote tumor vascularization which facilitates the migration and invasion of cancer cells to distant sites. VEGF; vascular endothelial growth factor.

Figure 3

STAT3 mediates reciprocal crosstalk between CAFs, tumor cells and immune cells in the TME. Cytokine-mediated activation of STAT3 promotes the transformation of normal fibroblasts to cancer associated fibroblasts (CAFs). STAT3 increases the expression of hypoxia-inducible factor-1 (HIF-1) that leads to hypoxia and autophagy. This results in the production of high energy products that fuel the tricarboxylic (TCA) cycle in tumor cells, as well as the production of IL-6 that form a positive feedback loop to enable further activation of CAFs. Moreover, elevated oxidative stress induced by tumor-derived reactive oxygen species (ROS) can induce genomic instability and promote tumor heterogeneity. On the other hand, STAT3-mediated activation of CAFs exert immunosuppressive effects via the recruitment and polarization of macrophages from an M1 to an M2 endotype, which suppresses the cytotoxic activity of natural killer (NK) cells. Moreover, CAFs recruit regulatory dendritic cells (DCregs) to inhibit the activation of cytotoxic T cells while simultaneously promoting the proliferation of regulatory T cells. IL-6/STAT3 signaling in CAFs also promotes the development of myeloid-derived suppressor cells (MDSCs) and induces PD-L1 expression in neutrophils. Collectively, deviation of cytokine mediated STAT3 activity in the TME alters the metabolic landscape of tumors and fosters an immunosuppressive environment that can evade immune clearance.