TGF-beta: a master immune regulator

Introduction: Transforming Growth Factor-Beta (TGF-beta) is a master regulator of numerous cellular functions including cellular immunity. In cancer, TGF-beta 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-beta 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-beta 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-beta 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-beta overexpression is a widespread and profoundly negative molecular hallmark in multiple tumor types. Expert Opinion: TGF-beta status may serve as a biomarker to predict responsiveness and as a therapeutic target to increase the activity of immunotherapies.