TY - JOUR
T1 - OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum
AU - van der Sluis, Tetje C.
AU - Beyrend, Guillaume
AU - van der Gracht, Esmé T. I.
AU - Abdelaal, Tamim
AU - Jochems, Simon P.
AU - Belderbos, Robert A.
AU - Wesselink, Thomas H.
AU - van Duikeren, Suzanne
AU - van Haften, Floortje J.
AU - Redeker, Anke
AU - Ouboter, Laura F.
AU - Beyranvand Nejad, Elham
AU - Camps, Marcel
AU - Franken, Kees L. M. C.
AU - Linssen, Margot M.
AU - Hohenstein, Peter
AU - de Miranda, Noel F. C. C.
AU - Mei, Hailiang
AU - Bins, Adriaan D.
AU - Haanen, John B. A. G.
AU - Aerts, Joachim G.
AU - Ossendorp, Ferry
AU - Arens, Ramon
N1 - Funding Information: This research was funded by grants from the European Commission (Horizon 2020 MSCA grant under proposal number 675743 ; project acronym ISPIC), the Dutch Cancer Society (UL 2015–7817 to R.A.), and the LUMC Gisela Thier Fellowship (to T.C.v.d.S.). The authors acknowledge Dominique Veerkamp, Ward Vleeshouwers, Sander Keizer, Camilla Labrie, and Iris Pardieck for technical support; Yanling Xiao for help with analysis of the gene signatures; Jannie Borst and Thorbald van Hall for critically reviewing the manuscript; the Flow Cytometry Core Facility for technical support during sample acquisition and cell sorting; the Central Animal Facility for technical support; and Susan Kloet and Szymon Kielbasa for technical support with RNA sequencing analysis. Funding Information: This research was funded by grants from the European Commission (Horizon 2020 MSCA grant under proposal number 675743; project acronym ISPIC), the Dutch Cancer Society (UL 2015–7817 to R.A.), and the LUMC Gisela Thier Fellowship (to T.C.v.d.S.). The authors acknowledge Dominique Veerkamp, Ward Vleeshouwers, Sander Keizer, Camilla Labrie, and Iris Pardieck for technical support; Yanling Xiao for help with analysis of the gene signatures; Jannie Borst and Thorbald van Hall for critically reviewing the manuscript; the Flow Cytometry Core Facility for technical support during sample acquisition and cell sorting; the Central Animal Facility for technical support; and Susan Kloet and Szymon Kielbasa for technical support with RNA sequencing analysis. Conceptualization, R.A.; methodology, T.C.v.d.S. G.B. and R.A.; software, G.B. T.A. and S.P.J.; formal analysis, T.C.v.d.S. G.B. F.J.v.H. T.A. S.P.J. L.F.O. H.M. N.F.C.C.d.M. and R.A.; investigation, T.C.v.d.S. G.B. S.v.D. E.T.I.v.d.G. R.A.B. T.H.W. A.R. E.B.N. and M.C.; resources, M.M.L. P.H. A.D.B. J.B.A.G.H. J.G.A. and K.L.M.C.F.; writing – original draft, G.B. and R.A.; writing – review & editing, T.C.v.d.S. and R.A.; visualization, G.B. T.C.v.d.S. T.A. and S.P.J.; supervision, F.O. and R.A.; project administration, R.A.; funding acquisition, T.C.v.d.S. and R.A. The authors declare no competing interests. Publisher Copyright: © 2023 The Author(s)
PY - 2023/3/21
Y1 - 2023/3/21
N2 - Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.
AB - Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.
KW - T cells
KW - immune checkpoint therapy
KW - immunotherapy
KW - mass cytometry
KW - predictive biomarkers
KW - single-cell RNA sequencing
KW - systemic immune activation
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85149643400&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36796366
UR - http://www.scopus.com/inward/record.url?scp=85149643400&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.xcrm.2023.100939
DO - https://doi.org/10.1016/j.xcrm.2023.100939
M3 - Article
C2 - 36796366
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 3
M1 - 100939
ER -