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

Nature volume 610, pages 173–181 (2022)Cite this article

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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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Fig. 1: PD-1+TCF1+ stem-like CD8+ T cells provide the proliferative burst after PD-1 blockade, IL-2 therapy and PD-1 + IL-2 combination therapy during chronic LCMV infection.
Fig. 2: Distinct transcriptional signature of virus-specific CD8+ T cells after PD-1 + IL-2 combination therapy compared to PD-1 monotherapy during chronic LCMV infection.
Fig. 3: Phenotypic and functional characterization of LCMV-specific CD8+ T cells generated by PD-1 and IL-2 monotherapy and the combination therapy during chronic infection.
Fig. 4: Epigenetic signatures of LCMV-specific CD8+ T cells generated by IL-2 or PD-1 + IL-2 combination therapy are distinct from that by PD-1 monotherapy during chronic infection.
Fig. 5: CD25 blockade abrogates the synergy between IL-2 and PD-1 blockade.
Fig. 6: CD25 engagement by therapeutic IL-2 is crucial for the efficacy of PD-1 + IL-2 combination therapy.

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Data availability

All processed RNA-seq, scRNA-seq and ATAC-seq data supporting the findings of this study have been deposited at GEO under accession code GSE206739. Previously published Affymetrix microarrays (GEO: GSE9650)16, RNA-seq (NCBI BioProject: PRJNA412602)17 and ATAC-seq data (NCBI BioProject: PRJNA546023)30 are included for the analysis in this study. Source data are provided with this paper.

Code availability

Custom code for RNA-seq, scRNA-seq and ATAC-seq data analysis are available from the corresponding author on reasonable request.

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Acknowledgements

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 programme (ROADS grant 55440 funded by Roche, ID ROADS-034; to R.A.). We thank staff at the 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.

Author information

Authors and Affiliations

  1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA

    Masao Hashimoto, Koichi Araki, Haydn T. Kissick, William H. Hudson, Donald J. McGuire, Rebecca C. Obeng, Andreas Wieland, Judong Lee, Daniel T. McManus, James L. Ross, Se Jin Im, Junghwa Lee & Rafi Ahmed

  2. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA

    Masao Hashimoto, Koichi Araki, Haydn T. Kissick, William H. Hudson, Donald J. McGuire, Rebecca C. Obeng, Andreas Wieland, Judong Lee, Daniel T. McManus, James L. Ross, Se Jin Im, Junghwa Lee, Christopher D. Scharer & Rafi Ahmed

  3. Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Koichi Araki

  4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Koichi Araki

  5. Department of Urology, Emory University School of Medicine, Atlanta, GA, USA

    Maria A. Cardenas & Haydn T. Kissick

  6. Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA

    Peng Li, Jian-Xin Lin, Erin E. West & Warren J. Leonard

  7. Department of Immunology, Mayo Clinic School of Medicine and Sciences, Rochester, MN, USA

    Rohit R. Jadhav & Jorg J. Goronzy

  8. Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA

    Rohit R. Jadhav, Bin Hu & Jorg J. Goronzy

  9. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Haydn T. Kissick, Suresh S. Ramalingam & Rafi Ahmed

  10. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA

    Rebecca C. Obeng

  11. Department of Pathology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Rebecca C. Obeng

  12. Department of Otolaryngology, The Ohio State University College of Medicine, Columbus, OH, USA

    Andreas Wieland

  13. The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Andreas Wieland

  14. Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea

    Se Jin Im

  15. Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea

    Junghwa Lee

  16. Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA

    Erin E. West

  17. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Gordon J. Freeman

  18. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Gordon J. Freeman

  19. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA

    Arlene H. Sharpe

  20. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

    Arlene H. Sharpe

  21. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Suresh S. Ramalingam

  22. Biogen, Cambridge, MA, USA

    Alex Pellerin

  23. Roche Innovation Center Basel, Basel, Switzerland

    Volker Teichgräber

  24. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA

    William J. Greenleaf

  25. Roche Innovation Center Zurich, Schlieren, Switzerland

    Christian Klein & Pablo Umaña

  26. Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, New York, NY, USA

    Kendall A. Smith

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  1. Masao Hashimoto
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Contributions

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. analysed 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. analysed RNA-seq data. M.A.C., H.T.K. and D.J.M. analysed scRNA-seq data. R.R.J., W.J.G. and J.J.G. analysed ATAC-seq data. G.J.F., A.H.S., A.P., V.T., C.K., P.U. and K.A.S. contributed materials. M.H. and R.A. wrote the manuscript. All of the authors contributed to writing the manuscript and provided feedback.

Corresponding author

Correspondence to Rafi Ahmed.

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Competing interests

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.

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Nature thanks Stephen Jameson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 PD-1 + IL-2 combination therapy synergistically expands functional LCMV-specific CD8+ T cells that mediate viral control during chronic infection.

a, Experimental setup for panels b–e. Mice chronically infected with LCMV were either left untreated, or treated with anti-PD-L1 antibody alone (200 μg i.p., every 3 days), IL-2 therapy alone (15,000 IU i.p., twice daily), or the combination therapy for 2 weeks. b, Numbers of DbGP33+ CD8+ T cells in the indicated tissues and blood (per 1 x 106 PBMCs). c, d, Spleen cells were stimulated with pools of LCMV-specific peptides for 5 h and analysed by intracellular staining of cytokines (c) and degranulation (d). e, Viral titre in the indicated tissues. f, Experimental setup for panels g–i. LCMV chronically infected mice were either left untreated, or treated with combination therapy, or combination therapy plus anti-CD8 depleting antibody (200 μg i.p., every 3 days) for 2 weeks. g, Viral titre in the indicated tissues of the three groups of mice. h, i, Correlation between viral titre in the various tissues and the number of CD8+ T cells (h), or LCMV-specific (DbGP33+ and DbGP276+) CD8+ T cells (i). Results were pooled from 3-13 experiments (b–e) with n = 25-32 (spleen), n = 14-18 (liver), n = 7-8 (lung), and n = 20-33 (blood) (b), with n = 28-38 (IFNγ+), n = 28-38 (IFNγ+TNFα+), n = 16-23 (IFNγ+IL-2+), and n = 18-25 (CD107a+) (c), and with n = 16-19 (spleen), n = 12-15 (liver), and n = 13-14 (lung) (e) per group or pooled from 2-3 experiments with 2-4 mice per group in each experiment (g–i). Data are presented as geometric mean and 95% CI (b–d), mean and SD (e, g), or linear regression line and Pearson correlation coefficient (two-tailed) (h, i) with p values. Statistical comparisons were performed using Kruskal-Wallis test with Dunn’s multiple-comparison test (b–d) or one-way ANOVA with Tukey’s multiple-comparison test (e). Untx, untreated

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Extended Data Fig. 2 The proliferative response after PD-1 blockade, IL-2 therapy, and PD-1 + IL-2 combination therapy comes from the same population of PD-1+ TCF1+ stem-like CD8+ T cells.

a, Gating strategy for sorting stem-like (PD-1+CXCR5+TIM3−) and exhausted (PD-1+CXCR5−TIM3+) CD8+ T-cell subsets isolated from spleens of CD45.2+ LCMV chronically infected mice. b–d, Summary data for the numbers of donor CD45.2+ CD8+ T cells after 2 weeks of PD-1 therapy, IL-2 therapy, and the combination therapy in liver (b), lungs (c), and blood (per 1 x 106 PBMCs) (d) of the recipient mice. Results were pooled from 3-4 experiments with n = 7-9 (PD-1 therapy), n = 5-13 (IL-2 therapy), and n = 5-11 (PD-1 + IL-2 combination therapy) per group. Data are presented as geometric mean and 95% CI (b–d) with p values. Dotted line indicates the limit of detection. Statistical comparisons were performed by using two-tailed unpaired Mann-Whitney test. AF, Alexa Fluor; EF, eFluor; Tx, treated; Untx, untreated

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Extended Data Fig. 3 Transcriptional profiling of LCMV-specific CD8+ T cells generated by PD-1 monotherapy, IL-2 treatment, and PD-1 + IL-2 combination therapy during chronic infection.

Mice chronically infected with LCMV were treated with PD-1 monotherapy, IL-2 alone, or combination therapy for 2 weeks. LCMV-specific DbGP33+ CD8+ T cells from spleens of each treatment group were sorted for RNA-seq (a–d) and scRNA-seq (e–j). As a control, naive (CD44lo) CD8+ T cells were also sorted for scRNA-seq (e–j). a, MA plots for gene expression of DbGP33+ CD8+ T cells after the indicated treatments. b–d, GSEA of DbGP33+ CD8+ T cells generated by the indicated treatments for effector signature (acute infection) (b), memory signature (acute infection) (c), and exhaustion signature (chronic infection) (d). e, The t-SNE projection of naive CD44lo CD8+ T cells and DbGP33+ CD8+ T cells in 4 treatment groups during chronic infection. Naive and four treatment samples were distributed and overlaid onto the four clusters. f, Numbers of cells in clusters 1, 2, and 3. g, Numbers of cells in cluster 1. Numbers of total DbGP33+ CD8+ T cells per spleen were estimated from geometric mean of Extended Data Fig. 1b (f, g). h, Normalized expression of several representative genes is shown within the 4 clusters i, Co-expression patterns of Tcf7 and Gzmb in cells of each cluster are shown. j, GSEA of DbGP33+ CD8+ T cells generated by the different treatments for effector signature (acute infection) and exhaustion signature (chronic infection). Enrichment score for the signature in four treatment samples are shown as violin plots with horizontal bars of mean. Results were pooled from 2 (a–d) and 1-2 (e–j) experiments with n = 2-18 mice per group in each experiment. ES, enrichment score; Untx, untreated.

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Extended Data Fig. 4 Phenotypic and functional analysis of LCMV-specific CD8+ T cells generated by PD-1, IL-2, and combination therapy during chronic infection.

LCMV chronically infected mice were either left untreated, or treated with anti-PD-L1 antibody alone, IL-2 therapy alone, or the combination therapy for 2 weeks. a, Representative FACS plots for co-expression of TIM3 and various phenotypic markers on DbGP33+ CD8+ T cells in spleens. b, c, One million splenocytes were cultured with recombinant mouse IL-12 and IL-18 (20 ng ml−1 each) for 5 h, then GolgiPlug was added, followed by culturing for 1 h. Note that no viral peptides were added to the culture. Cells were stained with surface markers including DbGP33-specific tetramer, fixed, and followed by intracellular staining of IFNγ. b, Representative FACS plots for co-staining of CD218a and IFNγ gated on DbGP33+ CD8+ T cells after the indicated treatments. c, Summary plots for the frequency of IFNγ+ cells in DbGP33+ CD8+ T cells. Results shown are representative flow plots from 2-7 experiments (a, b) or pooled from 7 experiments (c) with n = 2-5 per group in each experiment. Data are presented as mean and SD with p values (c). Statistical comparisons were performed using one-way ANOVA with Tukey’s multiple-comparison test (c). AF, Alexa Fluor; EF, eFluor; Untx, untreated.

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Extended Data Fig. 5 Identification of LCMV-specific CD8+ T cells generated after PD-1, IL-2, and combination therapy that produce cytokine after peptide stimulation.

LCMV chronically infected mice were either left untreated, or treated with anti-PD-L1 antibody alone, IL-2 therapy alone, or the combination therapy for 2 weeks. Spleen cells were stimulated with pools of LCMV-specific peptides for 5 h and analysed by intracellular staining for cytokine production. a, Representative UMAP with FlowSOM overlay of DbGP33+ CD8+ T cells isolated from spleens after the indicated treatments shows the distribution of cells in three clusters. b, Summary data for numbers of IFNγ+ LCMV-specific CD8+ T cells in the defined 3 clusters in the different treatment groups is shown. Results were pooled from 4 experiments with 2-3 mice per group in each experiment. Data are presented as mean and SEM (b) with p values. Statistical comparisons were performed using Kruskal-Wallis test with Dunn’s multiple-comparison test (d, e). Untx, untreated.

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Extended Data Fig. 6 Chromatin accessibility profiling of LCMV-specific CD8+ T cells in acute and chronic infection and after PD-1 treatment, IL-2 or PD-1 + IL-2 combination therapy.

a, Gene annotations of differentially accessible distal regulatory regions in DbGP33+ CD8+ T cells of mice treated with anti-PD-L1 and PD-1 + IL-2 combination therapy. The number of differentially open gene regulatory regions for genes of functional importance in DbGP33+ CD8+ T cells after PD-1 monotherapy vs. PD-1 + IL-2 combination therapy is shown. b, Accessibility tracks for representative genes in LCMV-specific DbGP33+ CD8+ T cells generated by various treatments during chronic infection. Light blue lines beneath each panel indicate differentially accessible regions in DbGP33+ CD8+ T cells generated by PD-1 therapy versus PD-1 + IL-2 combination therapy. Red dotted lines highlight the regions indicated by the light blue lines. c, Heat map with 10 clusters generated by using k-means clustering of 16,758 DARs among DbGP33+ CD8+ T cells generated by the combination therapy. Then, naive CD8+ T cells and various LCMV-specific CD8+ T-cell subsets during acute and chronic infections were incorporated into the heat map. Results were pooled from 3 experiments of ATAC-seq with n = 12-18 for untreated mice or n = 1-3 for treatment samples per group in each experiment. ATAC-seq data for naive, acute (memory precursor (MP), terminal effector (TE), and memory), and chronic (stem-like and exhausted) was from our previous study30. Untx, untreated.

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Extended Data Fig. 7 Importance of PD-1/PD-L1 blockade at the target site in reducing viral load during chronic LCMV infection.

a, Experimental design. Mice chronically infected with LCMV were divided into two groups; one group was treated with IL-2 only for 13 days (IL-2 group), and the second group was given IL-2 for 10 days followed by 2 doses of anti-PD-L1 antibody on days 10 and 12 (IL-2 + late anti-PD-L1 group). Mice were then analysed at day 14 for LCMV-specific CD8+ T-cell responses, viral titre, and liver immunopathlogy. b, Numbers of LCMV-specific (DbGP33+ and DbGP276+) CD8+ T cells. c, Viral titre in the indicated tissues. d–f, Immunopathological assessment. Serum levels of alanine aminotransferase (ALT) (d), liver pathology score (e), and number of TUNEL+ sinusoidal cells and hepatocytes (f). Results were pooled from 2-4 experiments with n = 2-5 per group in each experiment (b–f). For serum ALT levels, serum samples were pooled from 2-3 mice. TUNEL staining was done on one of the representative experiments with n = 4 per group. Data are presented as geometric mean and 95% CI (b) or mean and SD (c–f) with p values. Statistical comparisons were performed using two-tailed unpaired Mann-Whitney test (b), or two-tailed unpaired t-test (c–f). ALT, alanine aminotransferase. TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling.

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Extended Data Fig. 8 PD-1 + IL-2 combination therapy results in a more favourable CD8+ effector/CD4+ Treg ratio compared to IL-2 monotherapy.

Mice chronically infected with were either left untreated, or treated with anti-PD-L1 antibody alone, IL-2 therapy alone, or combination therapy. a, Numbers of FOXP3+ CD4+ regulatory T cells (Tregs) in the indicated tissues. b, Numbers of LCMV-specific (DbGP33+ and DbGP276+) CD8+ T cells. c, Ratio of LCMV-specific (DbGP33+ and DbGP276+) CD8+ T cells vs. FOXP3+ CD4+ T cells (CD8+ effector/CD4+ Treg ratio). d, Correlation between viral titre and CD8+ effector/CD4+ Treg ratio in the various tissues. Results were pooled from 5-8 experiments with n = 2-4 per group in each experiment. Data are presented as geometric mean and 95% CI (a, b), mean and SEM (c), or linear regression line and Pearson correlation coefficient (two-tailed) (d) with p values. Statistical comparisons were performed using Kruskal-Wallis test with Dunn’s multiple-comparison test (a–c). Untx, untreated.

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Extended Data Fig. 9 PD-1+TCF1+ stem-like CD8+ T cells proliferate and differentiate into effector CD8+ T cells expressing the high affinity trimeric (CD25, CD122, CD132) IL-2 receptor after PD-1 + IL-2 combination therapy.

a, Experimental setup for panels b–d. Stem-like (PD-1+CXCR5+Tim-3−) and exhausted (PD-1+CXCR5−TIM3+) CD8+ T-cell subsets were sorted from the spleens of LCMV chronically infected CD45.2+ mice and each subset was transferred into infection-matched CD45.1+ recipient mice. Groups of these mice were then either left untreated, given anti-PD-L1 antibody, IL-2 therapy, or combination therapy for 2 weeks. CD25 expression on donor CD45.2+ CD8+ T cells was checked before and after the treatments. b, Representative histogram of CD25 expression on the chronic CD8+ T-cell subsets pre-transfer. Naive (CD44lo) CD8+ T cells are also shown as a negative control. c, d, Representative FACS plots of CD25 expression and summary data of frequency of CD25+ cells in donor CD45.2+ CD8+ T cells originating from stem-like or exhausted CD8+ T cells after the indicated treatments. e, Experimental setup for panels f–o. LCMV chronically infected mice were treated with anti-PD-L1 antibody, IL-2 alone, or combination therapy. Mice were sacrificed on the indicated days and expression of CD25, CD122 and CD132 was examined on LCMV-specific CD8+ T cells in the spleen. f, Representative flow plots for the co-expression of CD25 and Ki-67 on DbGP33+ CD8+ T cells at day 0 or day 6 after treatment. g, j, m, Representative histograms showing the expression of CD25 (g), CD122 (j), and CD132 (m) on stem-like and exhausted LCMV-specific DbGP33+ subsets CD8+ T cells before starting the treatment of LCMV chronically infected mice. Naive cells are CD44lo CD8+ T cells present in the same host. h, k, n, Representative histograms showing the expression of CD25 (h), CD122 (k), and CD132 (n) on DbGP33+ CD8+ T cells at days 0-6 after starting the indicated treatment. i, l, o, Summary box plots for the frequency of CD25+ cells (i), MFI of CD122 (l) and MFI of CD132 (o) on DbGP33+ CD8+ T cells after the indicated treatments. Results were pooled from 2-5 experiments with at least 4 mice per group (a–o). Data are presented as mean and SD (d) or the box (25th to 75th percentiles), the whiskers (min to max), and the line (the median) (i, l, o) with p values. Statistical comparisons were performed using one-way ANOVA with Tukey’s multiple-comparison test. Untx, untreated.

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Extended Data Fig. 10 IL-2(V) does not synergize with PD-1 blockade during chronic LCMV infection.

LCMV chronically infected mice were left untreated, or treated with anti-PD-L1 antibody, anti-PD-L1 plus IL-2 wild-type (IL-2(WT)), or anti-PD-L1 plus IL-2(V) (modified IL-2 with abolished CD25 binding) for 2 weeks. a, Numbers of DbGP276+ CD8+ T cells in the indicated tissues of the four groups of mice. b, Numbers of DbGP33+ and DbGP276+ CD8+ T cells in blood (per 1x 106 PBMCs) in the four groups. c, Numbers of IFNγ+ CD8+ T cells in the different groups. Spleen cells were stimulated with pools of LCMV-specific peptides for 5 h and analysed by intracellular cytokine staining. d, Summary data for the expression of various phenotypic markers on DbGP33+ and DbGP276+ CD8+ T cells after the different treatments. Results were pooled from 2-3 experiments with 2-3 mice per group in each experiment. Data are presented as geometric mean and 95% CI (a–c) or mean and SD (d) with p values. Statistical comparisons were performed using Kruskal-Wallis test with Dunn’s multiple-comparison test (a–c) or one-way ANOVA with Tukey’s multiple-comparison test (d). Untx, untreated.

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Extended Data Fig. 11 IL-2(V) is biologically active in vivo but PD-1 + IL-2v combination therapy preferentially expands non-LCMV-specific PD-1 negative CD8+ T cells.

a, Experimental setup for b–c. Mice chronically infected with LCMV were left untreated, or treated with IL-2(WT) or IL-2(V) (modified IL-2 with abolished CD25 binding) for 2 weeks. Expansion of CD8+ T cells was examined in the spleen and blood in the three groups of mice. b, Numbers of CD8+ T cells. c, Numbers of CD44+ CD8+ T cells. d, Experimental setup for panels e–g. Chronically infected mice were untreated, or treated with anti-PD-L1 antibody, anti-PD-L1 plus IL-2(WT), or anti-PD-L1 plus IL-2(V) for 2 weeks. Expansion of PD-1 negative and PD-1 positive CD8+ T cells was examined in the spleen and blood in the four groups of mice. e, Representative FACS plots for CD44 and PD-1 expression on CD8+ T cells in the spleen and blood after the various treatments. f, Numbers of CD44+ PD-1 negative CD8+ T cells in the spleen and blood. g, Numbers of CD44+ PD-1 positive CD8+ T cells in the spleen and blood (per 1×106 PBMCs) of the four groups. Results were pooled from 3 experiments with at least 6 mice per group. Data are presented as geometric mean and 95% CI (b, c, f, g) with p values. Red box highlights preferential expansion of PD-1 negative CD8+ T cells by combination therapy with anti-PD-L1 and IL-2(V) whereas combination therapy with anti-PD-L1 and IL-2(WT) expands PD-1 positive CD8+ T cells. Statistical comparisons were performed using Kruskal-Wallis test with Dunn’s multiple-comparison test. Untx, untreated.

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Extended Data Fig. 12 Effect of IL-2(WT) versus IL-2(V) on LCMV-specific CD8+ T cells during chronic infection.

a, Experimental design for data in panels b and c. Mice chronically infected with LCMV (> 40 days post infection) were untreated or treated with IL-2(WT) for 5 days, and CD25 expression was checked on PD-1negative and PD-1+ CD8+ T cells in the spleen. b, Representative FACS plots of CD25 expression. c, Summary plots of CD25 expression after IL-2(WT) and IL-2(V) treatments. d, Experimental design for data in panels e and f. Mice chronically infected with LCMV were untreated, treated with IL-2(WT) or treated with IL-2(V) for 6 days. Expression of IL-2 receptors (CD25, CD122, and CD132) on LCMV-specific CD8+ T cells in the spleen were examined. e, f, Representative histograms (e) and summary plots (f) of expression of IL-2 receptors on DbGP33+ CD8+ T cells after indicated treatments. Results were pooled from 2 experiments with 2-3 mice per group in each experiment. Data are presented as mean and SD (c, f) with p values. Statistical comparisons were performed using one-way ANOVA with Tukey’s multiple-comparison test. Untx, untreated.

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Extended Data Fig. 13 Comparing the effects of IL-2(WT) cytokine versus IL-2(V) cytokine in PD-1 combination therapy in the LCMV chronic infection model with CD4+ T-cell help.

a, Experimental design. Mice infected with LCMV clone 13 (day 25 post-infection) were left untreated, or treated with anti-PD-L1 antibody, anti-PD-L1 plus IL-2(WT), or anti-PD-L1 plus IL-2(V). b, Numbers of LCMV-specific DbGP33+ CD8+ T cells in the indicated tissues after the various treatments. c, Summary data for the expression of phenotypic markers on DbGP33+ or DbGP276+ CD8+ T cells in the spleen after the different treatments. d, Numbers of IFNγ+, and IFNγ+TNFα+ LCMV-specific CD8+ T cells in the four groups. Spleen cells were stimulated with pools of LCMV-specific peptides for 5 h and analysed by intracellular staining of cytokines e, Viral titre in spleen and serum in the four groups of mice. Dotted line indicates the limit of detection. Results were pooled from 3-4 experiments with 2-5 mice per group in each experiment. Data are presented as geometric mean and 95% CI (b, d) or mean and SD (c, e, f) with p values. Statistical comparisons were performed using Kruskal-Wallis test with Dunn’s multiple-comparison test (b, d, f (number of LCMV-specific CD4+ T cells)) or one-way ANOVA with Tukey’s multiple-comparison test (c, e, f (phenotype of LCMV-specific CD4+ T cells)). Untx, untreated.

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Supplementary Figs. 1–15, Supplementary Notes 1–3 and Supplementary Data 1–3. The Supplementary Notes include descriptions for Supplementary Data 1–3, including information on the statistical analyses.

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Hashimoto, M., Araki, K., Cardenas, M.A. et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature 610, 173–181 (2022). https://doi.org/10.1038/s41586-022-05257-0

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