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PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.
- Source :
- Nature; Oct2022, Vol. 610 Issue 7930, p173-181, 9p
- Publication Year :
- 2022
-
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<superscript>+</superscript>TCF1<superscript>+</superscript> stem-like CD8<superscript>+</superscript> T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8<superscript>+</superscript> T cells that resemble highly functional effector CD8<superscript>+</superscript> T cells seen after an acute viral infection. The generation of these qualitatively superior CD8<superscript>+</superscript> T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1<superscript>+</superscript>TCF1<superscript>+</superscript> stem-like CD8<superscript>+</superscript> T cells, also referred to as precursors of exhausted CD8<superscript>+</superscript> 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<superscript>+</superscript> T cells emerging from the stem-like CD8<superscript>+</superscript> 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.PD-1<superscript>+</superscript>TCF1<superscript>+</superscript> stem-like CD8<superscript>+</superscript> T cells—precursors of exhausted CD8<superscript>+</superscript> T cells—are not fate-locked into the exhaustion program; their differentiation trajectory can be changed by IL-2 signals. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00280836
- Volume :
- 610
- Issue :
- 7930
- Database :
- Complementary Index
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 159512506
- Full Text :
- https://doi.org/10.1038/s41586-022-05257-0