Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program.
Animals
CD8-Positive T-Lymphocytes
/ immunology
Cell Line
Diacylglycerol Kinase
/ antagonists & inhibitors
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Lymphocyte Activation
/ immunology
Lymphocytes, Tumor-Infiltrating
/ immunology
Mice
Neoplasms, Experimental
/ immunology
Signal Transduction
/ drug effects
Combination
Diacylglycerol Kinase
Drug Therapy
Immunotherapy
Programmed Cell Death-1
T Lymphocytes
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
11
01
2021
accepted:
22
03
2021
pubmed:
11
4
2021
medline:
16
10
2021
entrez:
10
4
2021
Statut:
ppublish
Résumé
Antibody-based therapies blocking the programmed cell death-1/ligand-1 (PD-1/PD-L1) axis have provided unprecedent clinical success in cancer treatment. Acquired resistance, however, frequently occurs, commonly associated with the upregulation of additional inhibitory molecules. Diacylglycerol kinase (DGK) α limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGKα targeting restores cytotoxic function of chimeric antigen receptor and CD8 We used a human triple parameter reporter cell line to investigate DGKα contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGKα expression in the growth dynamics and systemic tumor-derived effects of a PD-1-related tumor model, the MC38 colon adenocarcinoma. We identify DGKα as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGKα function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGKα inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation. Our results indicate that DGKα inhibition could provide an important mechanism to revert exhausted T lymphocyte phenotypes and thus favor proper anti-tumor T cell responses. The cooperative effect observed after PD-1/PD-L1 and DGKα blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Antibody-based therapies blocking the programmed cell death-1/ligand-1 (PD-1/PD-L1) axis have provided unprecedent clinical success in cancer treatment. Acquired resistance, however, frequently occurs, commonly associated with the upregulation of additional inhibitory molecules. Diacylglycerol kinase (DGK) α limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGKα targeting restores cytotoxic function of chimeric antigen receptor and CD8
MATERIALS AND METHODS
METHODS
We used a human triple parameter reporter cell line to investigate DGKα contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGKα expression in the growth dynamics and systemic tumor-derived effects of a PD-1-related tumor model, the MC38 colon adenocarcinoma.
RESULTS
RESULTS
We identify DGKα as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGKα function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGKα inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation.
CONCLUSIONS
CONCLUSIONS
Our results indicate that DGKα inhibition could provide an important mechanism to revert exhausted T lymphocyte phenotypes and thus favor proper anti-tumor T cell responses. The cooperative effect observed after PD-1/PD-L1 and DGKα blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.
Identifiants
pubmed: 33837851
doi: 10.1007/s00262-021-02924-5
pii: 10.1007/s00262-021-02924-5
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Diacylglycerol Kinase
EC 2.7.1.107
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3277-3289Subventions
Organisme : MINECO
ID : PID2019-108357RB-I00
Organisme : MINECO
ID : BFU2016-77207-R
Organisme : Fundación Científica Asociación Española Contra el Cáncer (ES)
ID : AECC-1518
Organisme : Comunidad de Madrid
ID : IMMUNOTHERCAM Consortium B2017/BMD-3733
Organisme : Aplastic Anemia and MDS International Foundation
ID : AAMDSIF OPE01644
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Hamanishi J, Mandai M, Matsumura N et al (2016) PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol 21(3):462–473
doi: 10.1007/s10147-016-0959-z
Patsoukis N, Duke-Cohan JS, Chaudhri A et al (2020) Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun Biol. https://doi.org/10.1038/s42003-020-0845-0
doi: 10.1038/s42003-020-0845-0
pubmed: 32184441
pmcid: 7078208
Sun C, Mezzadra R, Schumacher TN (2018) Regulation and function of the PD-L1 checkpoint. Immunity 48(3):434–452. https://doi.org/10.1016/j.immuni.2018.03.014
doi: 10.1016/j.immuni.2018.03.014
pubmed: 29562194
pmcid: 7116507
Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856
doi: 10.1158/1535-7163.MCT-14-0983
Ahmadzadeh M, Johnson LA, Heemskerk B et al (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. https://doi.org/10.1182/blood-2008-12-195792
doi: 10.1182/blood-2008-12-195792
pubmed: 19423728
pmcid: 2927090
Quigley M, Pereyra F, Nilsson B et al (2010) Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. https://doi.org/10.1038/nm.2232
doi: 10.1038/nm.2232
pubmed: 20890291
pmcid: 3326577
Lynn RC, Weber EW, Sotillo E et al (2019) c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. https://doi.org/10.1038/s41586-019-1805-z
doi: 10.1038/s41586-019-1805-z
pubmed: 31802004
pmcid: 6944329
Edmead CE, Patel YI, Wilson A et al (1996) Induction of activator protein (AP)-1 and nuclear factor-κB by CD28 stimulation involves both phosphatidylinositol 3-kinase and acidic sphingomyelinase signals. J Immunol 157(8):3290–3297
pubmed: 8871623
Hui E, Cheung J, Zhu J et al (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. https://doi.org/10.1126/science.aaf1292
doi: 10.1126/science.aaf1292
pubmed: 29146808
pmcid: 6286077
Baine I, Abe BT, Macian F (2009) Regulation of T-cell tolerance by calcium/NFAT signaling. Immunol, Rev
doi: 10.1111/j.1600-065X.2009.00817.x
Arranz-Nicolás J, Ogando J, Soutar D et al (2018) Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals. Cancer Immunol Immunother. https://doi.org/10.1007/s00262-018-2154-8
doi: 10.1007/s00262-018-2154-8
pubmed: 29572701
Zhong XP, Hainey EA, Olenchock BA et al (2002) Regulation of T cell receptor-induced activation of the Ras-ERK pathway by diacylglycerol kinase ζ. J Biol Chem. https://doi.org/10.1074/jbc.M203818200
doi: 10.1074/jbc.M203818200
pubmed: 12468538
Goto K, Kondo H (1999) Diacylglycerol kinase in the central nervous system-molecular heterogeneity and gene expression. Chem Phys Lipids 98(1–2):109–117. https://doi.org/10.1016/s0009-3084(99)00023-7
doi: 10.1016/s0009-3084(99)00023-7
pubmed: 10358933
Shulga YV, Topham MK, Epand RM (2011) Regulation and functions of diacylglycerol kinases. Chem, Rev
doi: 10.1021/cr1004106
Mérida I, Andrada E, Gharbi SI, Ávila-Flores A (2015) Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions. Sci Signal. https://doi.org/10.1126/scisignal.aaa0974
doi: 10.1126/scisignal.aaa0974
pubmed: 25921290
Macián F, García-Cózar F, Im SH et al (2002) Transcriptional mechanisms underlying lymphocyte tolerance. Cell. https://doi.org/10.1016/S0092-8674(02)00767-5
doi: 10.1016/S0092-8674(02)00767-5
pubmed: 12086671
Martinez-Moreno M, Garcia-Lievana J, Soutar D et al (2012) FoxO-dependent regulation of diacylglycerol kinase gene expression. Mol Cell Biol. https://doi.org/10.1128/mcb.00654-12
doi: 10.1128/mcb.00654-12
pubmed: 22890845
pmcid: 3457341
Baldanzi G, Pighini A, Bettio V et al (2011) SAP-mediated inhibition of diacylglycerol kinase α regulates TCR-induced diacylglycerol signaling. J Immunol. https://doi.org/10.4049/jimmunol.1002476
doi: 10.4049/jimmunol.1002476
pubmed: 22048771
Ruffo E, Malacarne V, Larsen SE et al (2016) Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aad1565
doi: 10.1126/scitranslmed.aad1565
pubmed: 26764158
pmcid: 4918505
Prinz PU, Mendler AN, Masouris I et al (2012) High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8 + T cells that is reversible by pharmacologic intervention. J Immunol. https://doi.org/10.4049/jimmunol.1103028
doi: 10.4049/jimmunol.1103028
pubmed: 22869903
Moon EK, Wang LC, Dolfi DV et al (2014) Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-13-2627
doi: 10.1158/1078-0432.CCR-13-2627
pubmed: 24919573
pmcid: 4134701
Zhou P, Shaffer DR, Alvarez Arias DA et al (2014) In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature. https://doi.org/10.1038/nature12988
doi: 10.1038/nature12988
pubmed: 25409824
pmcid: 4266106
Riese MJ, Wang LCS, Moon EK et al (2013) Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-12-3874
doi: 10.1158/0008-5472.CAN-12-3874
pubmed: 23576561
pmcid: 3686869
Andrada E, Liébana R, Merida I (2017) Diacylglycerol kinase ζ limits cytokine-dependent expansion of CD8+ T cells with broad antitumor capacity. EBioMedicine. https://doi.org/10.1016/j.ebiom.2017.04.024
doi: 10.1016/j.ebiom.2017.04.024
pubmed: 28438506
pmcid: 5440620
Wesley EM, Xin G, McAllister D et al (2018) Diacylglycerol kinase ζ (DGKζ) and casitas b-lineage proto-oncogene b–deficient mice have similar functional outcomes in T cells but DGKζ-deficient mice have increased T cell activation and tumor clearance. Immuno Horizons. https://doi.org/10.4049/immunohorizons.1700055
doi: 10.4049/immunohorizons.1700055
Jutz S, Leitner J, Schmetterer K et al (2016) Assessment of costimulation and coinhibition in a triple parameter T cell reporter line: simultaneous measurement of NF-κB, NFAT and AP-1. J Immunol Methods. https://doi.org/10.1016/j.jim.2016.01.007
doi: 10.1016/j.jim.2016.01.007
pubmed: 26780292
Leitner J, Kuschei W, Grabmeier-Pfistershammer K et al (2010) T cell stimulator cells, an efficient and versatile cellular system to assess the role of costimulatory ligands in the activation of human T cells. J Immunol Methods. https://doi.org/10.1016/j.jim.2010.09.020
doi: 10.1016/j.jim.2010.09.020
pubmed: 20858499
pmcid: 2975062
Ávila-Flores A, Arranz-Nicolás J, Andrada E et al (2017) Predominant contribution of DGKζ over DGKα in the control of PKC/PDK-1-regulated functions in T cells. Immunol Cell Biol. https://doi.org/10.1038/icb.2017.7
doi: 10.1038/icb.2017.7
pubmed: 28163304
Gharbi SI, Rincón E, Avila-Flores A et al (2011) Diacylglycerol kinase ζ controls diacylglycerol metabolism at the immunological synapse. Mol Biol Cell. https://doi.org/10.1091/mbc.E11-03-0247
doi: 10.1091/mbc.E11-03-0247
pubmed: 21937721
pmcid: 3216665
Sanjuán MA, Jones DR, Izquierdo M, Mérida I (2001) Role of diacylglycerol kinase α in the attenuation of receptor signaling. J Cell Biol. https://doi.org/10.1083/jcb.153.1.207
doi: 10.1083/jcb.153.1.207
pubmed: 11285286
pmcid: 2185527
Olenchock BA, Guo R, Carpenter JH et al (2006) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol. https://doi.org/10.1038/ni1400
doi: 10.1038/ni1400
pubmed: 17028587
Arranz-Nicolás J, Martin-Salgado M, Rodríguez-Rodríguez C et al (2020) Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes. J Immunother Cancer. https://doi.org/10.1136/jitc-2020-001521
doi: 10.1136/jitc-2020-001521
pubmed: 33246984
pmcid: 7703416
Juneja VR, McGuire KA, Manguso RT et al (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med. https://doi.org/10.1084/jem.20160801
doi: 10.1084/jem.20160801
pubmed: 28302645
pmcid: 5379970
Meng X, Liu X, Guo X et al (2018) FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature 564(7734):130–135
doi: 10.1038/s41586-018-0756-0
Liu M, Jin X, He X et al (2015) Macrophages support splenic erythropoiesis in 4T1 tumor-bearing mice. PLoS ONE. https://doi.org/10.1371/journal.pone.0121921
doi: 10.1371/journal.pone.0121921
pubmed: 26720755
pmcid: 4703137
Zhao L, He R, Long H et al (2018) Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med. https://doi.org/10.1038/s41591-018-0205-5
doi: 10.1038/s41591-018-0205-5
pubmed: 30559421
pmcid: 6532069
Sanjuán MA, Pradet-Balade B, Jones DR et al (2003) T cell activation in vivo targets diacylglycerol kinase α to the membrane: a novel mechanism for Ras Attenuation. J Immunol. https://doi.org/10.4049/jimmunol.170.6.2877
doi: 10.4049/jimmunol.170.6.2877
pubmed: 12626583
Merino E, Ávila-Flores A, Shirai Y et al (2008) Lck-dependent tyrosine phosphorylation of diacylglycerol kinase α regulates its membrane association in T Cells. J Immunol. https://doi.org/10.4049/jimmunol.180.9.5805
doi: 10.4049/jimmunol.180.9.5805
pubmed: 18424699
Mahoney KM, Freeman GJ, McDermott DF (2015) The next immune-checkpoint inhibitors: Pd-1/pd-l1 blockade in melanoma. Clin, Ther
Rincón M, Flavell RA (1994) AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J. https://doi.org/10.1002/j.1460-2075.1994.tb06757.x
doi: 10.1002/j.1460-2075.1994.tb06757.x
pubmed: 7925281
pmcid: 395364
Kang SM, Beverly B, Tran AC et al (1992) Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. https://doi.org/10.1126/science.257.5073.1134
doi: 10.1126/science.257.5073.1134
pubmed: 1455226
Stelekati E, Chen Z, Manne S et al (2018) Long-term persistence of exhausted CD8 T cells in chronic infection is regulated by MicroRNA-155. Cell Rep. https://doi.org/10.1016/j.celrep.2018.04.038
doi: 10.1016/j.celrep.2018.04.038
pubmed: 29768211
pmcid: 5986283
Guo R, Wan CK, Carpenter JH et al (2008) Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.0711856105
doi: 10.1073/pnas.0711856105
pubmed: 19074282
pmcid: 2629309
Jung IY, Kim YY, Yu HS et al (2018) CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-18-0030
doi: 10.1158/0008-5472.CAN-18-0030
pubmed: 30563886
pmcid: 6191353
Prinz PU, Mendler AN, Brech D et al (2014) NK-cell dysfunction in human renal carcinoma reveals diacylglycerol kinase as key regulator and target for therapeutic intervention. Int J Cancer. https://doi.org/10.1002/ijc.28837
doi: 10.1002/ijc.28837
pubmed: 24615391
Yang E, Singh BK, Paustian AMS, Kambayashi T (2016) Diacylglycerol kinase ζ Is a target to enhance NK cell function. J Immunol. https://doi.org/10.4049/jimmunol.1600581
doi: 10.4049/jimmunol.1600581
pubmed: 28039299
pmcid: 5253435
Boroda S, Niccum M, Raje V et al (2017) Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists. Biochem Pharmacol. https://doi.org/10.1016/j.bcp.2016.10.011
doi: 10.1016/j.bcp.2016.10.011
pubmed: 27974147
Velnati S, Ruffo E, Massarotti A et al (2019) Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening. Eur J Med Chem. https://doi.org/10.1016/j.ejmech.2018.12.061
doi: 10.1016/j.ejmech.2018.12.061
pubmed: 30611057
Fu L, Li S, Xiao W et al (2021) DGKA mediates resistance to PD-1 blockade. Cancer Immunol Res. https://doi.org/10.1158/2326-6066.CIR-20-0216
doi: 10.1158/2326-6066.CIR-20-0216
pubmed: 34285037
Franks CE, Campbell ST, Purow BW et al (2017) The ligand binding landscape of Diacylglycerol kinases. Cell Chem Biol. https://doi.org/10.1016/j.chembiol.2017.06.007
doi: 10.1016/j.chembiol.2017.06.007
pubmed: 28712745
pmcid: 5551460
Jiang Y, Sakane F, Kanoh H, Walsh JP (2000) Selectivity of the diacylglycerol kinase inhibitor 3-{2-(4-[bis-(4-fluorophenyl)methylene]-1-piperidinyl)ethyl}-2,3-dihydro-2-thioxo-4(1H)quinazolinone (R59949) among diacylglycerol kinase subtypes. Biochem Pharmacol. https://doi.org/10.1016/S0006-2952(99)00395-0
doi: 10.1016/S0006-2952(99)00395-0
pubmed: 11077052
pmcid: 5567773