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CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype

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Abstract

Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8+ T-cell responses against Epstein–Barr virus (EBV) and Hepatitis B virus (HBV), and that T cells primed by CD137L-DCs more effectively lyse EBV+ and HBV+ target cells. The chemokine profile of CD137L-DCs identifies them as inflammatory DCs, and they polarize CD8+ T cells to a Tc1 phenotype. Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L-DCs possessing a stronger T cell activation ability. CD137L-DCs are effective in crosspresentation. PGE2 as a maturation factor is required for enhancing migration of CD137L-DCs but does not significantly reduce their potency. This study shows that CD137L-DCs have a superior ability to activate T cells and to induce potent Tc1 responses against the cancer-causing viruses EBV and HBV which suggest CD137L-DCs as promising candidates for DC-based tumor immunotherapy.

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Abbreviations

CD137L:

CD137 ligand

CD137L-DC:

CD137 ligand-generated dendritic cell

cDC:

Classical DC

DC:

Dendritic cell

EBNA:

Epstein–Barr virus nuclear antigen

EBV:

Epstein–Barr virus

ECAR:

Extracellular acidification rate

HBsAG:

HBV surface antigen

HBV:

Hepatitis B virus

LMP-1:

Latent membrane protein

NUS:

National University of Singapore

OCR:

Oxygen consumption rate

PGE2:

Prostaglandin E2

References

  1. Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258

    Article  PubMed  CAS  Google Scholar 

  2. Palucka K, Banchereau J (2013) Dendritic-cell-based therapeutic cancer vaccines. Immunity 39:38–48. https://doi.org/10.1016/j.immuni.2013.07.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bol KF, Schreibelt G, Gerritsen WR, de Vries IJ, Figdor CG (2016) Dendritic Cell-based immunotherapy: state of the art and beyond. Clin Cancer Res 22:1897–1906. https://doi.org/10.1158/1078-0432.CCR-15-1399

    Article  PubMed  CAS  Google Scholar 

  4. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN (2014) Clinical use of dendritic cells for cancer therapy. Lancet Oncol 15:e257–267. https://doi.org/10.1016/S1470-2045(13)70585-0

    Article  PubMed  CAS  Google Scholar 

  5. Louis CU, Straathof K, Bollard CM, Ennamuri S, Gerken C, Lopez TT, Huls MH, Sheehan A, Wu MF, Liu H, Gee A, Brenner MK, Rooney CM et al (2010) Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother 33:983–990. https://doi.org/10.1097/CJI.0b013e3181f3cbf4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Smith C, Tsang J, Beagley L, Chua D, Lee V, Li V, Moss DJ, Coman W, Chan KH, Nicholls J, Kwong D, Khanna R (2012) Effective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res 72:1116–1125. https://doi.org/10.1158/0008-5472.can-11-3399

    Article  PubMed  CAS  Google Scholar 

  7. Lin CL, Lo WF, Lee TH, Ren Y, Hwang SL, Cheng YF, Chen CL, Chang YS, Lee SP, Rickinson AB, Tam PK (2002) Immunization with Epstein-Barr Virus (EBV) peptide-pulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer Res 62:6952–6958

    PubMed  CAS  Google Scholar 

  8. Qasim W, Brunetto M, Gehring AJ, Xue SA, Schurich A, Khakpoor A, Zhan H, Ciccorossi P, Gilmour K, Cavallone D, Moriconi F, Farzhenah F, Mazzoni A et al (2014) Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol 62:486–491. https://doi.org/10.1016/j.jhep.2014.10.001

    Article  PubMed  CAS  Google Scholar 

  9. Kwajah MMS, Schwarz H (2010) CD137 ligand signaling induces human monocyte to dendritic cell differentiation. Eur J Immunol 40:1938–1949. https://doi.org/10.1002/eji.200940105

    Article  CAS  Google Scholar 

  10. Harfuddin Z, Kwajah S, Chong Nyi Sim A, Macary PA, Schwarz H (2013) CD137L-stimulated dendritic cells are more potent than conventional dendritic cells at eliciting cytotoxic T-cell responses. Oncoimmunology 2:e26859. https://doi.org/10.4161/onci.26859

    Article  PubMed  PubMed Central  Google Scholar 

  11. Harfuddin Z, Dharmadhikari B, Wong SC, Duan K, Poidinger M, Kwajah S, Schwarz H (2016) Transcriptional and functional characterization of CD137L-dendritic cells identifies a novel dendritic cell phenotype. Sci Rep 6:29712. https://doi.org/10.1038/srep29712

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Shao Z, Schwarz H (2011) CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J Leukoc Biol 89:21–29. https://doi.org/10.1189/jlb.0510315

    Article  PubMed  CAS  Google Scholar 

  13. Drenkard D, Becke FM, Langstein J, Spruss T, Kunz-Schughart LA, Tan TE, Lim YC, Schwarz H (2007) CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity. FASEB J 21:456–463. https://doi.org/10.1096/fj.05-4739com

    Article  PubMed  CAS  Google Scholar 

  14. Broll K, Richter G, Pauly S, Hofstaedter F, Schwarz H (2001) CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am J Clin Pathol 115:543–549. https://doi.org/10.1309/6U88-357U-UKJ5-YPT3

    Article  PubMed  CAS  Google Scholar 

  15. Quek BZ, Lim YC, Lin JH, Tan TE, Chan J, Biswas A, Schwarz H (2010) CD137 enhances monocyte-ICAM-1 interactions in an E-selectin-dependent manner under flow conditions. Mol Immunol 47:1839–1847. https://doi.org/10.1016/j.molimm.2009.11.010

    Article  PubMed  CAS  Google Scholar 

  16. Jiang D, Chen Y, Schwarz H (2008) CD137 induces proliferation of murine hematopoietic progenitor cells and differentiation to macrophages. J Immunol 181:3923–3932

    Article  PubMed  CAS  Google Scholar 

  17. Jiang D, Yue PS, Drenkard D, Schwarz H (2008) Induction of proliferation and monocytic differentiation of human CD34 + cells by CD137 ligand signaling. Stem Cells 26:2372–2381. https://doi.org/10.1634/stemcells.2008-0158

    Article  PubMed  CAS  Google Scholar 

  18. Jiang D, Schwarz H (2010) Regulation of granulocyte and macrophage populations of murine bone marrow cells by G-CSF and CD137 protein. PLoS One 5:e15565. https://doi.org/10.1371/journal.pone.0015565

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Chauvin JM, Larrieu P, Sarrabayrouse G, Prevost-Blondel A, Lengagne R, Desfrancois J, Labarriere N, Jotereau F (2012) HLA anchor optimization of the melan-A-HLA-A2 epitope within a long peptide is required for efficient cross-priming of human tumor-reactive T cells. J Immunol 188:2102–2110. https://doi.org/10.4049/jimmunol.1101807

    Article  PubMed  CAS  Google Scholar 

  20. Jurgens LA, Khanna R, Weber J, Orentas RJ (2006) Transduction of primary lymphocytes with Epstein-Barr virus (EBV) latent membrane protein-specific T-cell receptor induces lysis of virus-infected cells: A novel strategy for the treatment of Hodgkin’s disease and nasopharyngeal carcinoma. J Clin Immunol 26:22–32. https://doi.org/10.1007/s10875-006-6532-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Gehring AJ, Xue SA, Ho ZZ, Teoh D, Ruedl C, Chia A, Koh S, Lim SG, Maini MK, Stauss H, Bertoletti A (2011) Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J Hepatol 55:103–110. https://doi.org/10.1016/j.jhep.2010.10.025

    Article  PubMed  CAS  Google Scholar 

  22. Jonuleit H, Kuhn U, Muller G, Steinbrink K, Paragnik L, Schmitt E, Knop J, Enk AH (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27:3135–3142. https://doi.org/10.1002/eji.1830271209

    Article  PubMed  CAS  Google Scholar 

  23. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550. https://doi.org/10.1146/annurev.immunol.021908.132612

    Article  PubMed  CAS  Google Scholar 

  24. Lebre MC, Burwell T, Vieira PL, Lora J, Coyle AJ, Kapsenberg ML, Clausen BE, De Jong EC (2005) Differential expression of inflammatory chemokines by Th1- and Th2-cell promoting dendritic cells: a role for different mature dendritic cell populations in attracting appropriate effector cells to peripheral sites of inflammation. Immunol Cell Biol 83:525–535. https://doi.org/10.1111/j.1440-1711.2005.01365.x

    Article  PubMed  CAS  Google Scholar 

  25. Garg AD, Vandenberk L, Koks C, Verschuere T, Boon L, Van Gool SW, Agostinis P (2016) Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci Transl Med 8:328ra27. https://doi.org/10.1126/scitranslmed.aae0105

    Article  PubMed  CAS  Google Scholar 

  26. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492–499

    Article  PubMed  CAS  Google Scholar 

  27. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP, Rathmell JC (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61–72. https://doi.org/10.1016/j.cmet.2014.05.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, Bryce PJ, Chandel NS (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225–236. https://doi.org/10.1016/j.immuni.2012.10.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Pearce EL, Poffenberger MC, Chang C-H, Jones RG (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454. https://doi.org/10.1126/science.1242454

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Gerriets VA, Rathmell JC (2012) Metabolic pathways in T cell fate and function. Trends Immunol 33:168–173. https://doi.org/10.1016/j.it.2012.01.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Jacobs SR, Herman CE, MacIver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC (2008) Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 180:4476–4486

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Van den Bergh JMJ, Smits E, Berneman ZN, Hutten TJA, De Reu H, Van Tendeloo VFI, Dolstra H, Lion E, Hobo W (2017) Monocyte-derived dendritic cells with silenced PD-1 ligands and transpresenting interleukin-15 stimulate strong tumor-reactive T-cell expansion. Cancer Immunol Res 5:710–715. https://doi.org/10.1158/2326-6066.CIR-16-0336

    Article  PubMed  CAS  Google Scholar 

  33. Van den Bergh JMJ, Smits ELJM., Versteven M, De Reu H, Berneman ZN, Van Tendeloo VFI, Lion E (2017) Characterization of interleukin-15-transpresenting dendritic cells for clinical use. J Immunol Res 2017:1975902. https://doi.org/10.1155/2017/1975902

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mitchell DA, Batich KA, Gunn MD, Huang M-N, Sanchez-Perez L, Nair SK, Congdon KL, Reap EA, Archer GE, Desjardins A, Friedman AH, Friedman HS, Herndon Ii JE et al (2015) Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519:366–369. https://doi.org/10.1038/nature14320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, Ly A, Lie W-R, Hildebrand WH, Mardis ER, Linette GP (2015) A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348:803–808. https://doi.org/10.1126/science.aaa3828

  36. Rosenblatt J, Stone RM, Uhl L, Neuberg D, Joyce R, Levine JD, Arnason J, McMasters M, Luptakova K, Jain S, Zwicker JI, Hamdan A, Boussiotis V et al (2016) Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci Transl Med 8:368ra171. https://doi.org/10.1126/scitranslmed.aag1298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Dovedi SJ, Lipowska-Bhalla G, Beers SA, Cheadle EJ, Mu L, Glennie MJ, Illidge TM, Honeychurch J (2016) Antitumor efficacy of radiation plus immunotherapy depends upon dendritic cell activation of effector CD8+ T Cells. Cancer Immunol Res 4:621–630. https://doi.org/10.1158/2326-6066.CIR-15-0253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Bukczynski J, Wen T, Watts TH (2003) Costimulation of human CD28- T cells by 4-1BB ligand. Eur J Immunol 33:446–454. https://doi.org/10.1002/immu.200310020

    Article  PubMed  CAS  Google Scholar 

  39. Bertram EM, Dawicki W, Sedgmen B, Bramson JL, Lynch DH, Watts TH (2004) A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T cell response to influenza in vivo. J Immunol 172:981–988

    Article  PubMed  CAS  Google Scholar 

  40. Dharmadhikari B, Wu M, Abdullah NS, Rajendran S, Ishak ND, Nickles E, Harfuddin Z, Schwarz H (2016) CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses. Oncoimmunology 5:e1113367. https://doi.org/10.1080/2162402X.2015.1113367

    Article  PubMed  CAS  Google Scholar 

  41. Campana D, Schwarz H, Imai C (2014) 4-1BB chimeric antigen receptors. Cancer J 20:134–140. https://doi.org/10.1097/PPO.0000000000000028

    Article  PubMed  CAS  Google Scholar 

  42. Setareh M, Schwarz H, Lotz M (1995) A mRNA variant encoding a soluble form of 4-1BB, a member of the murine NGF/TNF receptor family. Gene 164:311–315

    Article  PubMed  CAS  Google Scholar 

  43. Michel J, Langstein J, Hofstadter F, Schwarz H (1998) A soluble form of CD137 (ILA/4-1BB),a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur J Immunol 28:290–295. https://doi.org/10.1002/(Sici)1521–4141(199801)28:01<290::Aid-Immu290>3.0.Co;2-S

  44. Shao Z, Sun F, Koh DR, Schwarz H (2008) Characterisation of soluble murine CD137 and its association with systemic lupus. Mol Immunol 45:3990–3999. https://doi.org/10.1016/j.molimm.2008.05.028

    Article  PubMed  CAS  Google Scholar 

  45. Furtner M, Straub RH, Kruger S, Schwarz H (2005) Levels of soluble CD137 are enhanced in sera of leukemia and lymphoma patients and are strongly associated with chronic lymphocytic leukemia. Leukemia 19:883–885. https://doi.org/10.1038/sj.leu.2403675

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank the Life Sciences Institute flow cytometry core facility for excellent assistance, and members of our laboratory for critical proofreading of the manuscript.

Funding

This research was supported by a Grant (NMRC/BnB/018b/2015) from the National Medical Research Council, Singapore.

Author information

Authors and Affiliations

  1. Department of Physiology and Immunology Programme, National University of Singapore (NUS), 2 Medical Dr., Singapore, 117593, Singapore

    Bhushan Dharmadhikari, Emily Nickles, Zulkarnain Harfuddin, Nur Diana Binte Ishak, Qun Zeng & Herbert Schwarz

  2. NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore

    Zulkarnain Harfuddin & Herbert Schwarz

  3. Duke-NUS Graduate Medical School, Singapore, 169857, Singapore

    Antonio Bertoletti

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  1. Bhushan Dharmadhikari
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  2. Emily Nickles
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  3. Zulkarnain Harfuddin
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  4. Nur Diana Binte Ishak
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  5. Qun Zeng
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  6. Antonio Bertoletti
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  7. Herbert Schwarz
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Contributions

Conception and design: Bhushan Dharmadhikari, Zulkarnain Harfuddin, and Herbert Schwarz. Development of methodology: Bhushan Dharmadhikari, Emily Nickles, and Zulkarnain Harfuddin. Acquisition of data: Bhushan Dharmadhikari, Emily Nickles, Zulkarnain Harfuddin, and Nur Diana Binte Ishak. Analysis and interpretation of data: Bhushan Dharmadhikari, Emily Nickles, Zulkarnain Harfuddin, Nur Diana Binte Ishak, Antonio Bertoletti, and Herbert Schwarz. Writing, review, and/or revision of the manuscript: Bhushan Dharmadhikari, Emily Nickles, Zulkarnain Harfuddin, Qun Zeng, Antonio Bertoletti, and Herbert Schwarz. Administrative, technical, or material support: Bhushan Dharmadhikari, Emily Nickles, Zulkarnain Harfuddin, Nur Diana Binte Ishak, Qun Zeng, and Antonio Bertoletti.

Corresponding author

Correspondence to Herbert Schwarz.

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This article does not contain any studies with human participants or animals performed by any of the authors. PBMC and monocytes were isolated from buffy coats of healthy volunteers, which were obtained from the Blood Donation Center of the National University Hospital, Singapore, after obtaining donors’ consent and approval by the NUS IRB (# B-15-320E). Cell lines used were newly purchased from ATCC (Manassas, VA, USA).

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Dharmadhikari, B., Nickles, E., Harfuddin, Z. et al. CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype. Cancer Immunol Immunother 67, 893–905 (2018). https://doi.org/10.1007/s00262-018-2144-x

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