Abstract
The induction of exhaustion on effector immune cells is an important limiting factor for cancer immunotherapy efficacy as these cells undergo a hierarchical loss of proliferation and cytolytic activity due to chronic stimulation. Targeting PD-1 has shown unprecedented clinical benefits for many cancers, which have been attributed to the prevention of immune suppression and exhaustion with enhanced anti-tumor responses. In this study, we sought to evaluate the role of the PD-1/PD-L1 pathway in murine natural killer (NK) cell activation, function, and exhaustion. In an in vivo IL-2-dependent exhaustion mouse model, neutralization of the PD-1/PD-L1 pathway improved NK cell activation after chronic stimulation when compared to control-treated mice. These cells displayed higher proliferative capabilities and enhanced granzyme B production. However, the blockade of these molecules during long-term in vitro IL-2 stimulation did not alter the progression of NK cell exhaustion (NCE), suggesting an indirect involvement of PD-1/PD-L1 on NCE. Given the expansion of CD8 T cells and regulatory T cells (Tregs) observed upon acute and chronic stimulation with IL-2, either of these two populations could influence NK cell homeostasis after PD-L1/PD-1 therapy. Importantly, CD8 T cell activation and functional phenotype were indeed enhanced by PD-1/PD-L1 therapy, particularly with anti-PD-1 treatment that resulted in the highest upregulation of CD25 during chronic stimulation and granted an advantage for IL-2 over NK cells. These results indicate a competition for resources between NK and CD8 T cells that arguably delays the onset of NCE rather than improving its activation during chronic stimulation. Supporting this notion, the depletion of CD8 T cells reversed the benefits of PD-1 therapy on chronically stimulated NK cells. These data suggest a bystander effect of anti-PD1 on NK cells, resulting from the global competition that exists between NK and CD8 T cells for IL-2 as a key regulator of these cells' activation. Thus, achieving an equilibrium between these immune cells might be important to accomplish long-term efficacy during anti-PD-1/IL-2 therapy.
Highlights
Natural killer (NK) cells are a subset of innate lymphocytes that have the property of destroying target cells without prior immune sensitization in an MHC unrestricted manner [1, 2]
We have demonstrated that chronic stimulation of natural killer (NK) cells leads to a phenotype characteristic of exhaustion defined by impaired function and downregulation of markers associated with activation and upregulation of inhibitory receptors
Because in the absence of Tregs we have seen an improvement in the activation and functional properties of CD8 T cells, likely due to the competition for cytokines between NK and CD8 T cells, we argue that PD-1/PD-L1 blockade might result in a similar phenomenon during chronic IL-2 treatment
Summary
Natural killer (NK) cells are a subset of innate lymphocytes that have the property of destroying target cells without prior immune sensitization in an MHC unrestricted manner [1, 2]. Exhaustion, described in both NK and T cells, represents a gradual process that causes a reduction in the proliferative and functional capacities of immune cells that can culminate in the elimination of the effector cells. This phenomenon has become a crucial component in the immune evasion mechanisms used by tumor and viruses to circumvent immune responses, as exhausted NK and T cells have been described after tumor exposure and chronic viral infections [7, 9,10,11]
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