PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program

Masao Hashimoto, Koichi Araki, Maria A. Cardenas, Peng Li, Rohit R. Jadhav, Haydn T. Kissick, William H. Hudson, Donald J. McGuire, Rebecca C. Obeng, Andreas Wieland, Judong Lee, Daniel T. McManus, James L. Ross, Se Jin Im, Junghwa Lee, Jian-Xin Lin, Bin Hu, Erin E. West, Christopher D. Scharer, Gordon J. Freeman, Arlene H. Sharpe, Suresh S. Ramalingam, Alex Pellerin, Volker Teichgräber, William J. Greenleaf, Christian Klein, Jorg J. Goronzy, Pablo Umaña, Warren J. Leonard, Kendall A. Smith and Rafi Ahmed ()
Additional contact information
Masao Hashimoto: Emory University School of Medicine
Koichi Araki: Emory University School of Medicine
Maria A. Cardenas: Emory University School of Medicine
Peng Li: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)
Rohit R. Jadhav: Mayo Clinic School of Medicine and Sciences
Haydn T. Kissick: Emory University School of Medicine
William H. Hudson: Emory University School of Medicine
Donald J. McGuire: Emory University School of Medicine
Rebecca C. Obeng: Emory University School of Medicine
Andreas Wieland: Emory University School of Medicine
Judong Lee: Emory University School of Medicine
Daniel T. McManus: Emory University School of Medicine
James L. Ross: Emory University School of Medicine
Se Jin Im: Emory University School of Medicine
Junghwa Lee: Emory University School of Medicine
Jian-Xin Lin: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)
Bin Hu: Stanford University School of Medicine
Erin E. West: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)
Christopher D. Scharer: Emory University School of Medicine
Gordon J. Freeman: Dana-Farber Cancer Institute
Arlene H. Sharpe: Blavatnik Institute, Harvard Medical School
Suresh S. Ramalingam: Emory University
Alex Pellerin: Biogen
Volker Teichgräber: Roche Innovation Center Basel
William J. Greenleaf: Stanford University School of Medicine
Christian Klein: Roche Innovation Center Zurich
Jorg J. Goronzy: Mayo Clinic School of Medicine and Sciences
Pablo Umaña: Roche Innovation Center Zurich
Warren J. Leonard: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)
Kendall A. Smith: Weill Medical College of Cornell University
Rafi Ahmed: Emory University School of Medicine

Nature, 2022, vol. 610, issue 7930, 173-181

Abstract: Abstract Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25–CD122–CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

Date: 2022
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DOI: 10.1038/s41586-022-05257-0

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