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

Nature. 2022 Oct;610(7930):173-181. doi: 10.1038/s41586-022-05257-0. Epub 2022 Sep 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes* / cytology
  • CD8-Positive T-Lymphocytes* / drug effects
  • CD8-Positive T-Lymphocytes* / immunology
  • Cell Differentiation / drug effects
  • Drug Therapy, Combination
  • Humans
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-2 Receptor beta Subunit
  • Interleukin-2* / immunology
  • Interleukin-2* / pharmacology
  • Interleukin-2* / therapeutic use
  • Lymphocytic Choriomeningitis / drug therapy
  • Lymphocytic Choriomeningitis / immunology
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • T Cell Transcription Factor 1


  • Interleukin Receptor Common gamma Subunit
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-2 Receptor beta Subunit
  • Programmed Cell Death 1 Receptor
  • T Cell Transcription Factor 1