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

Amr Allam,Jennifer Huynh,Lokman Pang,Matthias Ernst,Marina Yakou

doi:10.3389/fimmu.2021.767939

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.

Highlights

Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
The reactive oxygen species (ROS)/signal transducer and activator of transcription 3 (STAT3) signaling axis has been reported to induce tumor progression in pancreatic, prostate and liver cancers [39, 75, 76]. These findings indicate that STAT3-dependent cancer-associated fibroblasts (CAFs)-induced autophagy in response to oxidative stress is imposed by tumor cells
These findings indicate that CAF-dendritic cells (DC) crosstalk via IL-6/STAT3 promotes immunosuppression and tumor progression via either directly suppressing effector T cell activation or indirectly by promoting T regulatory cells (Tregs) expansion and subsequent effector T cell inactivation

Summary

CAFS IN TUMOR DEVELOPMENT

During the wound healing and regenerative response, normal fibroblasts play a critical role in maintaining tissue homeostasis after injury, where they trans-differentiate into a subtype of fibroblasts called myofibroblasts which induce force-mediated contractility and the deposition of ECM components, such as collagen I–IV, XVIII, proteoglycans, glycosaminoglycans (GAGs) and hyaluronic acid (HA) [10, 11]. IL-6 neutralizing antibodies and STAT3 inhibitors blocked the ability for CAFs to modulate the function of DCregs These findings indicate that CAF-DC crosstalk via IL-6/STAT3 promotes immunosuppression and tumor progression via either directly suppressing effector T cell activation or indirectly by promoting Treg expansion and subsequent effector T cell inactivation. The FGFR receptor inhibitor, Futibatinib, is being tested in a Phase II clinical trial for its activity in combination with the anti-PD-1 antibody, Pembrolizumab, for the treatment of advanced urothelial carcinoma (NCT04601857) Another approach to target CAFs is by intercepting their ability to produce and remodel the ECM [120, 121] which would in effect, dismantle the physical barrier that prevents immune cells from penetrating tumors and compromise the scaffold that would otherwise support tumor cell-CAF crosstalk. The anti-MMP-9 monoclonal antibody, GS-5745, is in Phase I testing in combination with immunotherapy (Bevacizumab) for the treatment of glioblastoma (NCT03631836)

Ipilimumab and Nivolumab Atezolizumab Trastuzumab and chemotherapy

CONCLUSION