Blockade of TGF-β signaling: a potential target for cancer immunotherapy?

ABSTRACT

Introduction: Malignant tumors often escape surveillance and eventual destruction by the host immune system through a variety of strategies including production of transforming growth factor (TGF)-β. Because of its generally immunosuppressive role, TGF-β has emerged as a promising therapeutic target in cancer immunotherapy.

Areas covered: This article looks at specific mechanisms of how TGF-β controls the function of various immune cell subsets in the tumor microenvironment and focusses on T-cells. Various inhibition tools of TGF-β signaling and potential targets of therapeutic intervention are assessed along with the recent progress in combining TGF-β blockade and immune-mediated therapies. To round off the article, a summary of results from clinical trials is provided in which TGF-β blockade has shown therapeutic benefit for patients.

Expert opinion: Data from preclinical models have shown that blocking TGF-β signaling can overcome resistance mechanisms and in combination with immune-checkpoint therapies, can yield additive or synergistic anti-tumor responses. The future of immunooncology will therefore be based on combination trials. Since response rates may critically depend on both cancer type and stage, selection of only those patients who can benefit from combinatorial immunotherapy regimens is of utmost importance.

KEYWORDS:

• Cancer
• immunotherapy
• signaling
• T-cell
• TGF-β
• tumor microenvironment

Article Highlights

• TGF-β is present in the tumor microenvironment in high concentrations because of production by both cancer, stromal and immune cells. It orchestrates the interplay between these cells and altogether adversely impacts cancer prognosis.

• TGF-β affects the biology of most types of immune cells in the tumor microenvironment. It controls T-cell fate decisions like development, differentiation, activation, proliferation, survival, and cytotoxicity.

• Generally, TGF-β acts to block the anticancer immune response by inhibiting the function of effector cells cells and at the same time promoting that of immune cells with a regulatory/suppressive function.

• Inhibition of TGF-β provides a powerful strategy to improve several aspects of the anti-cancer immune response such as T-cell priming within the lymph nodes, cytotoxic destruction of tumor cells, generation of suppressive immune cells, and suppression of EMT, invasion and metastatic dissemination of tumor cells.

• The response to TGF-β blockade and possible side effects associated with it depend on both cancer type and stage (‘TGF-β paradox’) and therefore careful selection of patients is required.

• Various TGF-β inhibitors used as either independent agents or in combination with various immunotherapeutic strategies are currently evaluated in preclinical animal models for their ability to enhance the efficacy of tumor immunotherapy.

• This box summarizes key points contained in the article.

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