Rethinking immune checkpoint blockade: 'Beyond the T cell'

Abstract

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

Keywords: CTLA-4 Antigen; immunity; immunotherapy; innate; programmed cell death 1 receptor; tumor microenvironment.

Figure 1

Direct and indirect regulation of innate immune subsets by PD-1 blockade. The regulation of innate immune cells by PD-1 blockade is divided into direct (left) and indirect (right) pathways. In the direct pathway, PD-1 blockade reshapes the phenotypes and functions of innate immune subsets, such as TAMs, DCs, MDSCs, NK cells, and ILC2s, expressing PD-1 (left). In the indirect pathway, T cells activated by anti-PD-1 secrete IFN-y, which in turn phenotypically polarizes myeloid cells within the TME (right). Bold arrows indicate interactions. DCs, dendritic cells; IFN-y, interferon gamma; ILCs, innate lymphoid cells; MDSCs, myeloid-derived suppressor cells: NK, natural killer cells; PD-1, programmed cell death protein 1; TAMs, tumor-associated macrophages; TEM, tumor microenvironment.

Figure 2

Direct and indirect signaling pathways downstream of PD-1 blockade in myeloid cells. PD-1 blockade results in direct (left) and indirect (right) signaling outcomes. Direct PD-1 blockade in PD-1 expressing myeloid cells activates NF-κB and pSTAT1 signaling pathways and reprograms glycometabolism (left). In the indirect pathway, anti-PD-1 activated T cells secrete IFN-y which triggers NF-κB and pSTAT1 signaling pathways in myeloid cells (right). Arrows indicate downstream outcomes of PD-1 blockade. IFN-γ, interferon gamma; PD-1, programmed cell death protein 1.