Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhauste...

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Published in:	Nature immunology Vol. 20; no. 3; pp. 326 - 336
Main Authors:	Miller, Brian C., Sen, Debattama R., Al Abosy, Rose, Bi, Kevin, Virkud, Yamini V., LaFleur, Martin W., Yates, Kathleen B., Lako, Ana, Felt, Kristen, Naik, Girish S., Manos, Michael, Gjini, Evisa, Kuchroo, Juhi R., Ishizuka, Jeffrey J., Collier, Jenna L., Griffin, Gabriel K., Maleri, Seth, Comstock, Dawn E., Weiss, Sarah A., Brown, Flavian D., Panda, Arpit, Zimmer, Margaret D., Manguso, Robert T., Hodi, F. Stephen, Rodig, Scott J., Sharpe, Arlene H., Haining, W. Nicholas
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.03.2019 Nature Publishing Group
Subjects:	631/250/1619/554/1834/1269 631/250/2502/2170 631/250/580 692/699/67/1059/2325 Animals Antibodies, Blocking - immunology Antibodies, Blocking - pharmacology Biomedical and Life Sciences Biomedicine CD8 antigen CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - virology Cell Line, Tumor Chronic infection Cytotoxicity Epigenetics Female Humans Immune checkpoint Immunology Infectious Diseases Lymphocyte Subsets - drug effects Lymphocyte Subsets - immunology Lymphocyte Subsets - virology Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - drug effects Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - virology Lymphocytic Choriomeningitis - immunology Lymphocytic Choriomeningitis - prevention & control Lymphocytic Choriomeningitis - virology Lymphocytic choriomeningitis virus - drug effects Lymphocytic choriomeningitis virus - immunology Lymphocytic choriomeningitis virus - physiology Melanoma Melanoma, Experimental - immunology Melanoma, Experimental - prevention & control Melanoma, Experimental - virology Mice, Congenic Mice, Inbred C57BL PD-1 protein Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - immunology Programmed Cell Death 1 Receptor - metabolism Transcription Tumor-infiltrating lymphocytes
ISSN:	1529-2908, 1529-2916, 1529-2916
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Summary:	T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8 + tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8 + TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8 + TILs include a subpopulation of ‘progenitor exhausted’ cells that retain polyfunctionality, persist long term and differentiate into ‘terminally exhausted’ TILs. Consequently, progenitor exhausted CD8 + TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8 + T cells might be an important component of improving the response to checkpoint blockade. Exhausted cytotoxic T lymphocytes (CTLs) express the receptor PD-1 as a key signature. Haining and colleagues show that there are different ‘depths’ of exhaustion with a subset of exhausted CTLs that retain polyfunctionality and are responsive to PD-1 blockade.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 J.J.I., J.L.C., A.P., S.M., D.E.C., S.A.W. and F.D.B. performed mouse experiments and/or data analysis. M.D.Z., R.T.M. and F.S.H. provided critical reagents. A.L., K.F., G.S.N., M.M., E.G., G.K.G., F.S.H. and S.J.R. collected human samples and data. B.C.M., D.R.S. and W.N.H. wrote the manuscript. All authors reviewed and edited the manuscript. B.C.M., D.R.S. and W.N.H. conceived the study. B.C.M., D.R.S., A.H.S. and W.N.H. designed the experiments. B.C.M., D.R.S., R.A.A., K.B., Y.V.V., M.W.L., K.B.Y., J.R.K. Author contributions
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-019-0312-6