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

• Type of Material: Article
• Authors: Masao Hashimoto, Emory University; Koichi Araki, Emory University; Maria A Cardenas, Emory University; Peng Li, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda; Rohit R Jadhav, Mayo Clinic; Haydn Kissick, Emory University; William Hudson, Emory University; Donald J McGuire, Emory University; Rebecca Obeng, Emory University; Andreas Wieland, Emory University; Judong Lee, Emory University; Daniel T McManus, Emory University; James L Ross, Emory University; Sejin Im, Emory University; Junghwa Lee, Emory University; Jian-Xin Lin, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda; Bin Hu, Stanford University; Erin E West, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda; Christopher Scharer, Emory University; Gordon J Freeman, Dana-Farber Cancer Institute, Boston; Arlene H Sharpe, Harvard Medical School; Suresh Ramalingam, Emory University; Alex Pellerin, Biogen; Volker Teichgraber, Roche Innovat Ctr Basel; William J Greenleaf, Stanford University; Christian Klein, Roche Innovat Ctr Zurich; Jorg J Goronzy, Mayo Clinic; Pablo Umana, Roche Innovat Ctr Zurich; Warren J Leonard, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda; Kendall A Smith, Cornell University; Rafi Ahmed, Emory University
• Language: English
• Date: 2022-09-28
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-022-05257-0
• Title of Journal or Parent Work: NATURE
• Volume: 610
• Issue: 7930
• Start Page: 173
• End Page: +
• Keywords: CHRONIC INFECTION; Multidisciplinary Sciences; EXPRESSION; Science & Technology - Other Topics; SIGNATURE; Science & Technology

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.