Targeting of the Cancer-Associated Fibroblast-T-Cell Axis in Solid Malignancies

Abstract

The introduction of a wide range of immunotherapies in clinical practice has revolutionized the treatment of cancer in the last decade. The majority of these therapeutic modalities are centered on reinvigorating a tumor-reactive cytotoxic T-cell response. While impressive clinical successes are obtained, the majority of cancer patients still fail to show a clinical response, despite the fact that their tumors express antigens that can be recognized by the immune system. This is due to a series of other cellular actors, present in or attracted towards the tumor microenvironment, including regulatory T-cells, myeloid-derived suppressor cells and cancer-associated fibroblasts (CAFs). As the main cellular constituent of the tumor-associated stroma, CAFs form a heterogeneous group of cells which can drive cancer cell invasion but can also impair the migration and activation of T-cells through direct and indirect mechanisms. This singles CAFs out as an important next target for further optimization of T-cell based immunotherapies. Here, we review the recent literature on the role of CAFs in orchestrating T-cell activation and migration within the tumor microenvironment and discuss potential avenues for targeting the interactions between fibroblasts and T-cells.

Keywords: T-cell based immunotherapy; cancer-associated fibroblast; tumor immunology.

Figure 1

Fibroblast heterogeneity in the tumor-microenvironment. (A–E). The origin of CAFs in the TME is diverse and they can be either derived from the activation of resident fibroblasts (A), endothelial-to-mesenchymal transition (EndoMT) (B), epithelial-to-mesenchymal transition (EMT) (C) bone-marrow derived mesenchymal cells (D) and/or other differential pathways (e.g., smooth muscle cell trans-differentiation (E)). (F,G). The function of these CAFs is diverse (F) and regulated by cues derived from within the TME, leading to formation of subsets with specific functions, including but not limited to, iCAFs (G). TGF-β, transforming growth factor β; ECM, extracellular matrix; CAF, cancer-associated fibroblast; iCAF, inflammatory CAF.

Figure 2

Therapeutic targeting of CAFs to enhance T-cell based immunotherapies. (A) Direct CAF targeting relies on the identification of CAF-selective targets to reduce ‘on-target off-CAF’ toxicity. RNA-sequencing based approaches enable identification of markers to target specific immunomodulatory CAF subsets. (B) Indirect CAF targeting relies on targeting of CAF-derived factors involved in T-cell exclusion and suppression. This can be done either through inhibiting CAF-derived cytokines involved in suppressing T-cell function (top-left), modulation of the ECM (top-right) or blocking of inhibitory chemotactic signals (e.g., TGF-β signaling) to improve accessibility of T-cells to the tumor (bottom-right) and/or inhibition of checkpoint molecules on CAFs or associated immune cells to potentiate tumoricidal T-cell effector functions (bottom-left). CAR, chimeric antigen receptor; FAP, fibroblast activation protein; CAF, cancer-associated fibroblast; iCAF, inflammatory CAF; IL-6, interleukin-6; ECM, extracellular matrix; TGF-β, transforming growth factor β.