Dual Transforming Growth Factor-β and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

Abstract

Tumors that elude infiltration by CD8⁺ T lymphocytes are particularly resistant to multiple forms of treatment, including immune checkpoint blockade. Stromal transforming growth factor (TGF)-β appears to play a key role in this process, potentially constituting a target for novel combinatorial regimens tackling immune-excluded neoplasms.

Keywords: PD-1; atezolizumab; microsatellite instability; mutational burden; tumor neoantigens; tumor organoids.

Figure 1. Blocking TGF-β enables therapeutic responses to ICBs in immune-excluded tumors

Immune-excluded tumors are characterized by the accumulation of CD8⁺ cytotoxic T lymphocytes (CTLs) at the tumor periphery, with limited infiltration of malignant cell nests. Some (but not all) of these tumors also exhibit a robust desmoplastic stroma characterized by high amounts of cancer-associated fibroblasts (CAFs) and a dense extracellular matrix (A). In this setting, immunotherapy with immune checkpoint blockers (ICBs) employed as standalone interventions generally provides limited clinical benefits as (re-)activated CTLs cannot get in contact with (and hence kill) malignant cells (B). Since transforming growth factor beta (TGF-β) produced by CAFs is etiologically involved in the establishment of immune exclusion, therapeutic regimens combining ICBs with an agent that inhibit TGF-β signaling, such as galunisertib or fresolimumab, may exert superior clinical benefits by simultaneously enabling T-cell activation and tumor infiltration (C).