Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment

Abstract

Checkpoint blockade therapy has been proven to be highly active across many cancer types but emerging evidence indicates that the therapeutic benefit is limited to a subset of patients in each cancer entity. The presence of CD8(+) T cells within the tumor microenvironment or the invasive margin of the tumor, as well as the up-regulation of PD-L1, have emerged to be the most predictive biomarkers for clinical benefit in response to checkpoint inhibition. Although the up-regulation of immune inhibitory mechanisms is one mechanism of immune escape, commonly used by T-cell-inflamed tumors, exclusion of an anti-tumor specific T-cell infiltrate displays another even more potent mechanism of immune escape. This review will contrast the mechanisms of immunogenic, T-cell-inflamed, and the novel concept of non-immunogenic, non-T-cell-inflamed, adaptive immune escape.

Keywords: checkpoint blockade; immune evasion; immunotherapy; oncogenes.

Fig. 1.

Induction of a potent and productive anti-tumor immune response. In Phase 1 (innate immune activation) APC, in particular CD8α⁺CD103⁺ DC, migrate into the tumor and produce IFN-α/β downstream of Sting activation. In Phase 2 (activation of antigen-specific T cells) in the TdLN, migratory CD8α⁺CD103⁺ DC deliver tumor-derived antigens to the TdLN and through cross-presentation activate tumor-specific CD8⁺ T cells. In Phase 3 (recruitment of activated T cells) subsequent to activation of effector T cells, those cells migrate into the tumor microenvironment via CXCL9/CXCL10 chemokine gradients.

Fig. 2.

Immune escape in a T-cell-inflamed tumor microenvironment. The figure shows details of the four dominant immune escape mechanisms in the T-cell-inflamed tumor microenvironment: PD-L1 up-regulation and subsequent inhibition of T cells through PD-L1 engagement with PD-1; IDO up-regulation; recruitment of regulatory T cells (Tregs) through CCL22 (derived from effector T cells); and selection of tumor cells with reduced antigenic immunogenicity.

Fig. 3.

Immune escape in a non-T-cell-inflamed tumor microenvironment. The figure depicts the three main mechanisms of immune escape through potent T-cell exclusion from the tumor microenvironment: a lack of innate immune cell recruitment, which results in a block of T-cell activation; oncogenic pathways that alter the tumor microenvironment in thus far ill-defined mechanisms but which exclude T cells; and a lack of effector T-cell recruitment due to loss of effector chemokine production.