Rescue of Exhausted CD8 T Cells by PD-1-targeted Therapies is CD28-dependent

Overview

Journal Science

Specialty Science

Date 2017 Mar 11

PMID 28280249

Citations 511

Authors

Alice O Kamphorst

Andreas Wieland

Tahseen Nasti

Shu Yang

Ruan Zhang

Daniel L Barber

Bogumila T Konieczny

Candace Z Daugherty

Lydia Koenig

Ke Yu

Gabriel L Sica

Arlene H Sharpe

Gordon J Freeman

Bruce R Blazar

Laurence A Turka

Taofeek K Owonikoko

Rathi N Pillai

Suresh S Ramalingam

Koichi Araki

Rafi Ahmed

Affiliations

Soon will be listed here.

Abstract

Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.

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References

Callahan M, Postow M, Wolchok J . Targeting T Cell Co-receptors for Cancer Therapy. Immunity. 2016; 44(5):1069-78. DOI: 10.1016/j.immuni.2016.04.023. View

Hui E, Cheung J, Zhu J, Su X, Taylor M, Wallweber H . T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017; 355(6332):1428-1433. PMC: 6286077. DOI: 10.1126/science.aaf1292. View

Spranger S, Bao R, Gajewski T . Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015; 523(7559):231-5. DOI: 10.1038/nature14404. View

Tumeh P, Harview C, Yearley J, Shintaku I, Taylor E, Robert L . PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515(7528):568-71. PMC: 4246418. DOI: 10.1038/nature13954. View

Butte M, Keir M, Phamduy T, Sharpe A, Freeman G . Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007; 27(1):111-22. PMC: 2707944. DOI: 10.1016/j.immuni.2007.05.016. View

Matloubian M, Concepcion R, Ahmed R . CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol. 1994; 68(12):8056-63. PMC: 237269. DOI: 10.1128/JVI.68.12.8056-8063.1994. View

Weng N, Akbar A, Goronzy J . CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009; 30(7):306-12. PMC: 2801888. DOI: 10.1016/j.it.2009.03.013. View

Moreno B, Zaretsky J, Garcia-Diaz A, Tsoi J, Parisi G, Robert L . Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells. Cancer Immunol Res. 2016; 4(10):845-857. PMC: 5050168. DOI: 10.1158/2326-6066.CIR-16-0060. View

Mueller S, Vanguri V, Ha S, West E, Keir M, Glickman J . PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J Clin Invest. 2010; 120(7):2508-15. PMC: 2898584. DOI: 10.1172/JCI40040. View

10.

Barber D, Wherry E, Masopust D, Zhu B, Allison J, Sharpe A . Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2005; 439(7077):682-7. DOI: 10.1038/nature04444. View

11.

Miller J, van der Most R, Akondy R, Glidewell J, Albott S, Masopust D . Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity. 2008; 28(5):710-22. DOI: 10.1016/j.immuni.2008.02.020. View

12.

Greenwald R, Freeman G, Sharpe A . The B7 family revisited. Annu Rev Immunol. 2005; 23:515-48. DOI: 10.1146/annurev.immunol.23.021704.115611. View

13.

Keir M, Butte M, Freeman G, Sharpe A . PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26:677-704. PMC: 10637733. DOI: 10.1146/annurev.immunol.26.021607.090331. View

14.

Filaci G, Fenoglio D, Fravega M, Ansaldo G, Borgonovo G, Traverso P . CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol. 2007; 179(7):4323-34. DOI: 10.4049/jimmunol.179.7.4323. View

15.

Li Y, Liu S, Hernandez J, Vence L, Hwu P, Radvanyi L . MART-1-specific melanoma tumor-infiltrating lymphocytes maintaining CD28 expression have improved survival and expansion capability following antigenic restimulation in vitro. J Immunol. 2009; 184(1):452-65. DOI: 10.4049/jimmunol.0901101. View

16.

Eberlein J, Davenport B, Nguyen T, Victorino F, Sparwasser T, Homann D . Multiple layers of CD80/86-dependent costimulatory activity regulate primary, memory, and secondary lymphocytic choriomeningitis virus-specific T cell immunity. J Virol. 2011; 86(4):1955-70. PMC: 3302393. DOI: 10.1128/JVI.05949-11. View

17.

Floyd T, Koehn B, Kitchens W, Robertson J, Cheeseman J, Stempora L . Limiting the amount and duration of antigen exposure during priming increases memory T cell requirement for costimulation during recall. J Immunol. 2011; 186(4):2033-41. PMC: 3057172. DOI: 10.4049/jimmunol.1003015. View

18.

Chen D, Mellman I . Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39(1):1-10. DOI: 10.1016/j.immuni.2013.07.012. View

19.

Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S . Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity. 2016; 44(4):924-38. PMC: 4980762. DOI: 10.1016/j.immuni.2016.03.012. View

20.

Pauken K, Wherry E . Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015; 36(4):265-76. PMC: 4393798. DOI: 10.1016/j.it.2015.02.008. View