TGFβ biology in cancer progression and immunotherapy

Abstract

TGF beta signalling has key roles in cancer progression: most carcinoma cells have inactivated their epithelial antiproliferative response and benefit from increased TGF beta expression and autocrine TGF beta signalling through effects on gene expression, release of immunosuppressive cytokines and epithelial plasticity. As a result, TGF beta enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance. TGF beta released by cancer cells, stromal fibroblasts and other cells in the tumour microenvironment further promotes cancer progression by shaping the architecture of the tumour and by suppressing the antitumour activities of immune cells, thus generating an immunosuppressive environment that prevents or attenuates the efficacy of anticancer immunotherapies. The repression of TGF beta signalling is therefore considered a prerequisite and major avenue to enhance the efficacy of current and forthcoming immunotherapies, including in tumours comprising cancer cells that are not TGF beta responsive. Herein, we introduce the mechanisms underlying TGF beta signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms as well as the use of these approaches in cancer immunotherapies and their potential adverse effects. TGF beta released by cancer cells and other cells in the tumour microenvironment enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance as well as generating an immunosuppressive environment. The authors of this Review introduce the mechanisms underlying TGF beta signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms, in particular in the context of cancer immunotherapy.