PD-L1 checkpoint blockade promotes regulatory T cell activity that underlies therapy resistance

Mandy van Gulijk*, Anneloes van Krimpen, Sjoerd Schetters, Mike Eterman, Marit van Elsas, Joanne Mankor, Larissa Klaase, Marjolein de Bruijn, Menno van Nimwegen, Tim van Tienhoven, Wilfred van Ijcken, Louis Boon, Johan van der Schoot, Martijn Verdoes, Ferenc Scheeren, Sjoerd H. van der Burg, Bart N. Lambrecht, Ralph Stadhouders, Floris Dammeijer*, Joachim Aerts*Thorbald van Hall*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

Abstract

Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood. Here, we identified preferential activation and enhanced suppressive capacity of regulatory T cells (Treg cells) in αPD-L1 therapy-resistant solid tumor-bearing mice. Treg cell depletion reversed resistance to αPD-L1 with concomitant expansion of effector T cells. Moreover, we found that tumor-infiltrating Treg cells in human patients with skin cancer, and in patients with non-small cell lung cancer, up-regulated a suppressive transcriptional gene program after ICB treatment, which correlated with lack of treatment response. αPD-1/PD-L1-induced PD-1+ Treg cell activation was also seen in peripheral blood of patients with lung cancer and mesothelioma, especially in nonresponders. Together, these data reveal that treatment with αPD-1 and αPD-L1 unleashes the immunosuppressive role of Treg cells, resulting in therapy resistance, suggesting that Treg cell targeting is an important adjunct strategy to enhance therapeutic efficacy.

Original languageEnglish
Article numbereabn6173
JournalScience immunology
Volume8
Issue number83
DOIs
Publication statusPublished - 19 May 2023

Bibliographical note

Funding Information:
We would like to thank R. Hendriks for helpful discussions and S. Baart for the statistical assistance. In addition, we would like to acknowledge all involved technicians from the pulmonary medicine department and the animal facility at the Erasmus Medical Center and Leiden University Medical Center for valuable contributions to this project. M.v.G. is supported by the Mesothelioma Applied Research Foundation (MARF). S.H.v.d.B. is a recipient of the Oncode Institute base fund, and R.S. is supported by an Erasmus MC Fellowship, a Dutch Lung Foundation Junior Investigator grant (4.2.19.041JO), a Daniel den Hoed Foundation grant, and a VIDI grant (09150172010068) from the Dutch Research Council (NWO).

Funding Information:
Acknowledgments:W ewouldliketothankR.HendriksforhelpfuldiscussionsandS.Baartfor thestatisticalassistance.Inaddition,wewouldliketoacknowledgeallinvolvedtechnicians fromthepulmonarymedicinedepartmentandtheanimalfacilityattheErasmusMedical CenterandLeidenUniversityMedicalCenterforvaluablecontributionstothisproject. Funding:M.v.G.issupportedbytheMesotheliomaAppliedResearchFoundation(MARF). S.H.v.d.B.is a recipient of theOncode Institute base fund, and R.S. is supported byan Erasmus MCFellowship,aDutchLungFoundationJuniorInvestiga tor grant(4.2.19.041JO),aDanielden HoedFoundationgrant,andaVIDIgrant(09150172010068)fromtheDutchResearchCouncil (NWO).Authorcontributions:M.v.G.,F .D., T .v.H., andJ.A.designedtheexperiments.M.v.G., M.E.,L.K.,M.d.B.,M.v.N.,andT .v.T .performedmurineexperiments,andM.v.G.analyzedthedata. M.v.G.,A.v.K.,andR.S.performedtheRNAsequencinganalyses.L.B.providedtherapeuticαPD-L1antibody.J.v.d.S.,M.V ., andF .S. engineeredtheαCD25antibody.M.v.G.,F .D., T .v.H., andJ.A wrote the manuscript. All authors were involved in the critical review of the manuscript. All authors read and approved the manuscript. Competing Interests: The authors declare that theyhavenocompetinginterests.Dataandmaterialsavailability:OriginalRNAsequencing datahav ebeendepositedtoGEO:GSE176250.Alldataneededtoevaluatetheconclusionsin thepaperarepresentinthepaperortheSupplementaryMaterials.

Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.

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