TGF-β Inhibition and Immunotherapy: Checkmate

Abstract

Immune checkpoint therapy can induce durable remissions, but many tumors demonstrate resistance. In a recent issue of Nature, Mariathasan et al. (2018) and Tauriello et al. (2018) identify stromal TGF-β signaling as a determinant of immune exclusion. Combination TGF-β inhibition and immunotherapy induces complete responses in mouse models.

Figure 1. TGFβ inhibition induces tumor T-cell infiltration and potentiates response to immune checkpoint therapy

Expression of a fibroblast TGFβ response signature (F-TBRS) in peritumoral fibroblasts leads to T-cell sequestration away from the tumor mass. In the absence of physical proximity between cytototoxic T cells and tumor cells, immune checkpoint blockade with PD-1/PD-L1 inhibitors is ineffective. Pharmacological inhibition of TGFβ reverses such immune exclusion and facilitates CD8+ T cell infiltration into tumors. Combination of TGFβ inhibition with immune checkpoint blockade maximizes tumor regression with many tumor-bearing mice exhibiting a complete response. These findings lay the foundation for combination clinical trials in cancer patients whose tumors exhibit an immune exhibited phenotype.