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Email: rahmed@emory.edu

M.H., K.A., and R.A. designed experiments. M.H., K.A., R.C.O., A.W. Judong Lee, D.T.M., C.D.S, S.S.R., W.J.G., J.J.G., W.J.L., and R.A. analyzed the experiments. M.H., R.C.O., A.W. Judong Lee, D.T.M., J.L.R, C.D.S, S.J.I., Junghwa Lee, J.-X.L., B.H., and E.E.W. performed experiments. M.H. P.L., H.T.K., and W.H.H analyzed RNA-seq data. M.A.C., H.T.K., and D.J.M. analyzed scRNA-seq data. R.R.J., W.J.G., and J.J.G. analyzed ATAC-seq data. G.J.F., A.H.S., A.P., V.T., C.K., P.U., and K.A.S. contributed critical materials. M.H. and R.A. wrote the manuscript, with all authors contributing to writing and providing feedback.

This work was supported by National Institutes of Health (NIH) grants R01AI030048 (to R.A.), P01AI056299 (to R.A., G.J.F., and A.H.S.), P50CA101942 (to G.J.F. and A.H.S.), P01CA236749 (to G.J.F. and A.H.S.), R01AI129191 (to J.J.G.), P50CA217691 (to S.S.R, and R.A.), and the Roche pRED ROADS program (ROADS grant 55440 funded by Roche, ID ROADS-034; to R.A.). We thank Emory University School of Medicine Flow Cytometry Core (K. Fife and R. Karaffa), Yerkes Nonhuman Primate Genomics Core (K. Pellegrini and S. Bosinger; NIH P51OD011132), Emory Integrated Genomics Core (EIGC) Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI (L. Griffiths; 2P30CA138292-04), Cancer Tissue and Pathology Shared Resource Facility of the Winship Cancer Institute of Emory University and NIH/NCI (P30CA138292), and the Mouse Histology and Phenotyping Lab at the Northwestern University Robert H. Lurie Comprehensive Cancer Center and NIH/NCI (P30CA060553). W.H.H. is supported by NIH grant K99AI153736 and a Cancer Research Institute Irvington Postdoctoral Fellowship. S.J.I. is supported by National Research Foundation of Korea (NRF) grant 2020R1F1A1075668 funded by the Korean government (MSIT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

R.A. has patents related to PD-1 pathway (8,652,465 and 9,457,080) licensed to Roche. A.H.S has patents and pending royalties from Roche and Novartis on intellectual property on the PD-1 pathway (patent 7,432,059 with royalties paid from Roche, Merck, Bristol Myers Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis; patent 7,722,868 with royalties paid from Roche, Merck, Bristol Myers Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis; patents 8,652,465 and 9,457,080 licensed to Roche; patents 9,683,048, 9,815,898, 9,845,356, 10,202,454 and 10,457,733 licensed to Novartis; and patents 9,580,684, 9,988,452 and 10,370,446 issued to none). G.J.F. has patents and pending royalties on the PD-1-PD-L1 pathway from Roche, Merck MSD, Bristol Myers Squibb, Merck KGaA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic and Novartis (see Supplementary Data 4). G.J.F. has served on advisory boards for Roche, Bristol Myers Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Trillium, GV20 and Geode. G.J.F. has equity in Nextpoint, Triursus, Xios, iTeos, IgM, GV20 and Geode. V.T., C.K. and P.U. are employed by Roche with stock options. C.K. and P.U have a patent application with Roche: WO2012107417. The other authors declare no competing interests.

Subjects:

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • CHRONIC INFECTION
  • EXPRESSION
  • SIGNATURE

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

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Journal Title:

NATURE

Volume:

Volume 610, Number 7930

Publisher:

, Pages 173-+

Type of Work:

Article | Post-print: After Peer Review

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.
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