Immune suppressive mechanisms in the tumor microenvironment

Abstract

Effective immunotherapy, whether by checkpoint blockade or adoptive cell therapy, is limited in most patients by a key barrier: the immunosuppressive tumor microenvironment. Suppression of tumor-specific T cells is orchestrated by the activity of a variety of stromal myeloid and lymphoid cells. These often display inducible suppressive mechanisms that are triggered by the same anti-tumor inflammatory response that the immunotherapy intends to create. Therefore, a more comprehensive understanding of how the immunosuppressive milieu develops and persists is critical in order to harness the full power of immunotherapy of cancer.

Figure 1. Examples of constitutive and inducible suppressive mechanisms in the tumor microenvironment

T cells attempting to activate in the tumor microenvironment may face constitutive expression of PD-L1 and IDO by the tumor cells. Myeloid-derived suppressor cells (MDSCs) in the tumor may produce immunosuppressive nitric oxide (NO), arginase-I or reactive oxygen species (ROS). Tumor-associated macrophages may produce TGFβ and VEGF, which can be inhibitory for both T cells and dendritic cells. Activated Tregs can produce IL-10 and TGFβ, which may directly suppress T cells. Tregs may also inhibit expression of costimulatory ligands CD80 and CD86 on local DCs, thus rendering them ineffective and tolerizing antigen-presenting cells. As effector T cells attempt to activate, their production of IFNγ and other pro-inflammatory cytokines may actively up-regulate expression of IDO and PD-L1 by DCs, thus eliciting counter-regulatory suppression. Many tumor cells may also respond to IFNγ by up-regulating IDO and PD-L1.