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Original Research ARTICLE

Front. Immunol. | doi: 10.3389/fimmu.2020.00007

Indirect impact of PD-1/PD-L1 blockade on a murine model of NK cell exhaustion Provisionally accepted The final, formatted version of the article will be published soon. Notify me

 Maite Alvarez1, 2, 3*,  Federico Simonetta1,  Jeanette Baker1, Alyssa R. Morrison1, Arielle S. Wenokur1,  Antonio Pierini1,  Pedro Berraondo2, 3, 4 and  Robert Negrin1
  • 1Stanford University, United States
  • 2Center of Applied Medical Research, School of Pharmacy and Nutrition, University of Navarra, Spain
  • 3Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain
  • 4Center for Biomedical Research in Cancer Network (CIBERONC), Spain

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 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.

Keywords: NK, exhaustion, chronic stimulation, PD-1/PD-L1 pathway, CD8

Received: 08 Aug 2019; Accepted: 03 Jan 2020.

Copyright: © 2020 Alvarez, Simonetta, Baker, Morrison, Wenokur, Pierini, Berraondo and Negrin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Maite Alvarez, Stanford University, Stanford, United States,