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

• Authors: Rafi Ahmed, Emory University; Suresh Ramalingam, Emory University; Christopher Scharer, Emory University; Haydn Kissick, Emory University; Andreas Wieland, Emory University; Hal Scherz, Emory University; Masao Hashimoto, Emory University; William Hudson, Emory University; Rebecca Obeng, Emory University; Sejin Im, Emory University; K Araki, Emory University; MA Cardenas, Emory University; P Li, NHLBI; RR Jadhav, Mayo Clinic; DJ McGuire, Emory University; J Lee, Emory University; DT McManus, Emory University; JL Ross, Emory University; J Lee, Emory University; J-X Lin, NHLBI; B Hu, Stanford University; EE West, NHLBI; GJ Freeman, Dana Farber Canc Inst; AH Sharpe, Harvard Medical School; A Pellerin, Biogen; V Teichgraber, Roche Innovat Ctr Basel; WJ Greenleaf, Stanford University; C Klein, Roche Innovat Ctr Zurich; JJ Goronzy, Mayo Clinic; P Umana, Roche Innovat Ctr Zurich; WJ Leonard, NHLBI; KA Smith, Cornell University
• Journal Title: NATURE
• Volume: Volume 610, Number 7930
• Publisher: NATURE PORTFOLIO | 2022-09-28, Pages 173-+
• Type of Work: Article
• Publisher DOI: http://doi.org/10.1038/s41586-022-05257-0
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CHRONIC INFECTION; EXPRESSION; SIGNATURE

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.