TGF-beta: a master immune regulator

ABSTRACT

Introduction: Transforming Growth Factor-Beta (TGF-β) is a master regulator of numerous cellular functions including cellular immunity. In cancer, TGF-β can function as a tumor promoter via several mechanisms including immunosuppression. Since the immune checkpoint pathways are co-opted in cancer to induce T cell tolerance, this review posits that TGF-β is a master checkpoint in cancer, whose negative regulatory influence overrides and controls that of other immune checkpoints.

Areas Covered: This review examines therapeutic agents that target TGF-β and its signaling pathways for the treatment of cancer which may be classifiable as checkpoint inhibitors in the broadest sense. This concept is supported by the observations that 1) only a subset of patients benefit from current checkpoint inhibitor therapies, 2) the presence of TGF-β in the tumor microenvironment is associated with excluded or cold tumors, and resistance to checkpoint inhibitors, and 3) existing biomarkers such as PD-1, PD-L1, microsatellite instability and tumor mutational burden are inadequate to reliably and adequately identify immuno-responsive patients. By contrast, TGF-β overexpression is a widespread and profoundly negative molecular hallmark in multiple tumor types.

Expert Opinion: TGF-β status may serve as a biomarker to predict responsiveness and as a therapeutic target to increase the activity of immunotherapies.

KEYWORDS:

• Checkpoint Inhibitors
• immune regulation
• immunotherapy
• TGF-β

Article Highlights

• TGF-β tumor promotion affects multiple processes including angiogenesis, fibrosis and immunosuppression via effects on the tumor microenvironment.

• TGF-β acts at multiple steps to suppress the generation of anti-tumor immune responses.

• Data is presented that supports the hypothesis that TGF-β is a master immune checkpoint, whose immunosuppressive properties have the potential to negate or attenuate the activities of checkpoint inhibitors.

• There are multiple inhibitors of TGF-β in preclinical and clinical development that target TGF-β and its signaling pathways that are promising ‘universal’ checkpoint inhibitors for the treatment of cancer (e.g. small molecules, antibodies, antisense oligonucleotides, vaccines, oncolytic viruses).

• Given the favorable toxicity profile of these TGF-β inhibitors, combined with their ability to regulate checkpoint activity, they have the potential to synergistically enhance the efficacy of a variety of immunotherapies.

• In addition, TGF-β has the potential to serve as a predictive biomarker for response to cancer therapies.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.