Myeloid-driven mechanisms as barriers to antitumor CD8+ T cell activity

Abstract

The adaptive immune system is essential for host defense against pathogenic challenges, and a major constituent is the CD8⁺ cytotoxic T cell. Ordinarily, CD8⁺ T cells are endowed with a unique ability to specifically recognize and destroy their targets. However, in cases where disease emerges, especially in cancer, the efficacy of the CD8⁺ T cell response is frequently counterbalanced in a 'tug-of-war' by networks of tumor-driven mechanisms of immune suppression. As a result, antitumor CD8⁺ T cell activity is hampered, which contributes to clinical manifestations of disease. It is now well-recognized that prominent elements of that network include myeloid-derived suppressor cells (MDSC) and macrophages which assume tumor-supportive phenotypes. Both myeloid populations are thought to arise as consequences of chronic inflammatory cues produced during the neoplastic process. Numerous preclinical studies have now shown that inhibiting the production, trafficking and/or function of these immune suppressive myeloid populations restore antitumor CD8⁺ T cell responses during both immune surveillance or in response to immune-targeted interventions. Correlative studies in cancer patients support these preclinical findings and, thus, have laid the foundation for ongoing clinical trials in patients receiving novel agents that target such myeloid elements alone or in combination with immunotherapy to potentially improve cancer patient outcomes. Accordingly, this review focuses on how and why it is important to study the myeloid-T cell interplay as an innovative strategy to boost or reinvigorate the CD8⁺ T cell response as a critical weapon in the battle against malignancy.

Keywords: CD8(+) T cells; Immune suppression; Immunotherapy; Macrophages; Myeloid-derived suppressor cells.

Figure 1:. Suppression of CD8⁺ T cell activity by myeloid-derived suppressor cells (MDSC) and macrophages.

MDSC and macrophages may inhibit CD8⁺ T cell responses by secreting immunosuppressive cytokines such as IL-10 or TGF-β. Release of reactive oxygen or nitrogen species may be deleterious to CD8⁺ T cells within MDSC or macrophage proximity. Enzymatic activity within MDSC and macrophages influences nutrient availability for T cells. In particular, Arg1 and IDO reduce the abundance of L-arginine and tryptophan metabolites. Furthermore, direct contact of MDSC or macrophages with CD8⁺ T cells via the PD-L1-PD-1 axis promotes CD8⁺ T cell exhaustion and apoptosis. Macrophages may further downregulate CD8⁺ T cell lytic activity through the CD80/86-CTLA-4 axis. Lastly, MDSC may limit CD8⁺ T cell activation by cleaving a T cell trafficking molecule, L-selectin, reducing naïve CD8⁺ T cell recruitment to lymph nodes for subsequent antigen exposure.