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Journal of Neuro-Oncology

, Volume 142, Issue 3, pp 395–407 | Cite as

Monitoring of intracerebellarly-administered natural killer cells with fluorine-19 MRI

  • Bridget A. Kennis
  • Keith A. Michel
  • William B. Brugmann
  • Alvaro Laureano
  • Rong-Hua Tao
  • Srinivas S. Somanchi
  • Samuel A. Einstein
  • Javiera B. Bravo-Alegria
  • Shinji Maegawa
  • Andrew Wahba
  • Simin Kiany
  • Nancy Gordon
  • Lucia Silla
  • Dawid Schellingerhout
  • Soumen Khatua
  • Wafik Zaky
  • David Sandberg
  • Laurence Cooper
  • Dean A. LeeEmail author
  • James A. BanksonEmail author
  • Vidya GopalakrishnanEmail author
Laboratory Investigation

Abstract

Purpose

Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown.

Methods

To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored.

Results

The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F–labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry.

Conclusions

Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.

Keywords

Medulloblastoma NK-cell delivery Immunotherapy Fluorine-19 MRI 

Notes

Acknowledgements

This work was supported by funding support from Addis Faith Foundation, Noah’s Light Foundation, American Cancer Society Award Number 118165-RSG-09-273-01-DDC and the Rally Foundation for Childhood Cancers to VG.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human and animal participants

All animal experiments were approved by Institutional Animal Care and Use Committee (IACUC).

Supplementary material

11060_2019_3091_MOESM1_ESM.pdf (177 kb)
Supplementary material 1 (PDF 177 KB)
11060_2019_3091_MOESM2_ESM.pdf (100.1 mb)
Supplementary material 2 (PDF 102510 KB)
11060_2019_3091_MOESM3_ESM.pdf (246 kb)
Supplementary material 3 (PDF 246 KB)
11060_2019_3091_MOESM4_ESM.pdf (106 kb)
Supplementary material 4 (PDF 105 KB)

References

  1. 1.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109.  https://doi.org/10.1007/s00401-007-0243-4 CrossRefGoogle Scholar
  2. 2.
    Gerber NU, Mynarek M, von Hoff K, Friedrich C, Resch A, Rutkowski S (2014) Recent developments and current concepts in medulloblastoma. Cancer Treat Rev 40:356–365.  https://doi.org/10.1016/j.ctrv.2013.11.010 CrossRefGoogle Scholar
  3. 3.
    Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472.  https://doi.org/10.1007/s00401-011-0922-z CrossRefGoogle Scholar
  4. 4.
    Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, Lopez-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpena-Diazconti M, de Leon CPF, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, Taylor MD (2017) Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 31:737–754 e736.  https://doi.org/10.1016/j.ccell.2017.05.005 CrossRefGoogle Scholar
  5. 5.
    Carlotti CG Jr, Smith C, Rutka JT (2008) The molecular genetics of medulloblastoma: an assessment of new therapeutic targets. Neurosurg Rev 31:359–368.  https://doi.org/10.1007/s10143-008-0146-4 (discussion 368 – 359)CrossRefGoogle Scholar
  6. 6.
    Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers P, Krull K, Chintagumpala M, Stargatt R, Ashley DM, Tyc VL, Kun L, Boyett J, Gajjar A (2005) Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 23:5511–5519.  https://doi.org/10.1200/JCO.2005.00.703 CrossRefGoogle Scholar
  7. 7.
    Grob ST, Levy JMM (2017) Improving diagnostic and therapeutic outcomes in pediatric brain tumors. Mol Diagn Ther.  https://doi.org/10.1007/s40291-017-0299-3 Google Scholar
  8. 8.
    Castriconi R, Dondero A, Negri F, Bellora F, Nozza P, Carnemolla B, Raso A, Moretta L, Moretta A, Bottino C (2007) Both CD133 + and CD133- medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicity. Eur J Immunol 37:3190–3196.  https://doi.org/10.1002/eji.200737546 CrossRefGoogle Scholar
  9. 9.
    Fernandez L, Portugal R, Valentin J, Martin R, Maxwell H, Gonzalez-Vicent M, Diaz MA, de Prada I, Perez-Martinez A (2013) In vitro natural killer cell immunotherapy for medulloblastoma. Front Oncol 3:94.  https://doi.org/10.3389/fonc.2013.00094 CrossRefGoogle Scholar
  10. 10.
    Perez-Martinez A, Fernandez L, Diaz MA (2016) The therapeutic potential of natural killer cells to target medulloblastoma. Expert Rev Anticancer Ther 16:573–576.  https://doi.org/10.1080/14737140.2016.1184978 CrossRefGoogle Scholar
  11. 11.
    Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, Singh H, Hurton L, Maiti SN, Huls MH, Champlin RE, Cooper LJ, Lee DA (2012) Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 7:e30264.  https://doi.org/10.1371/journal.pone.0030264 CrossRefGoogle Scholar
  12. 12.
    Smyth MJ, Hayakawa Y, Takeda K, Yagita H (2002) New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2:850–861.  https://doi.org/10.1038/nrc928 CrossRefGoogle Scholar
  13. 13.
    van den Broek MF, Kagi D, Zinkernagel RM, Hengartner H (1995) Perforin dependence of natural killer cell-mediated tumor control in vivo. Eur J Immunol 25:3514–3516.  https://doi.org/10.1002/eji.1830251246 CrossRefGoogle Scholar
  14. 14.
    Smyth MJ, Thia KY, Cretney E, Kelly JM, Snook MB, Forbes CA, Scalzo AA (1999) Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol 162:6658–6662Google Scholar
  15. 15.
    Zhang C, Burger MC, Jennewein L, Genssler S, Schonfeld K, Zeiner P, Hattingen E, Harter PN, Mittelbronn M, Tonn T, Steinbach JP, Wels WS (2016) ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst 108  https://doi.org/10.1093/jnci/djv375
  16. 16.
    Alkins R, Burgess A, Kerbel R, Wels WS, Hynynen K (2016) Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival. Neuro Oncol 18:974–981.  https://doi.org/10.1093/neuonc/nov318 CrossRefGoogle Scholar
  17. 17.
    Jha P, Golovko D, Bains S, Hostetter D, Meier R, Wendland MF, Daldrup-Link HE (2010) Monitoring of natural killer cell immunotherapy using noninvasive imaging modalities. Cancer Res 70:6109–6113.  https://doi.org/10.1158/0008-5472.CAN-09-3774 CrossRefGoogle Scholar
  18. 18.
    Sta Maria NS, Barnes SR, Jacobs RE (2014) In vivo monitoring of natural killer cell trafficking during tumor immunotherapy. Magn Reson Insights 7:15–21.  https://doi.org/10.4137/MRI.S13145 Google Scholar
  19. 19.
    Bouchlaka MN, Ludwig KD, Gordon JW, Kutz MP, Bednarz BP, Fain SB, Capitini CM (2016) (19)F-MRI for monitoring human NK cells in vivo. Oncoimmunology 5:e1143996.  https://doi.org/10.1080/2162402X.2016.1143996 CrossRefGoogle Scholar
  20. 20.
    Zhang J, Chamberlain R, Etheridge M, Idiyatullin D, Corum C, Bischof J, Garwood M (2014) Quantifying iron-oxide nanoparticles at high concentration based on longitudinal relaxation using a three-dimensional SWIFT look-locker sequence. Magn Reson Med 71:1982–1988.  https://doi.org/10.1002/mrm.25181 CrossRefGoogle Scholar
  21. 21.
    Ruiz-Cabello J, Barnett BP, Bottomley PA, Bulte JW (2011) Fluorine (19F) MRS and MRI in biomedicine. NMR Biomed 24:114–129.  https://doi.org/10.1002/nbm.1570 CrossRefGoogle Scholar
  22. 22.
    Ahrens ET, Bulte JW (2013) Tracking immune cells in vivo using magnetic resonance imaging. Nat Rev Immunol 13:755–763.  https://doi.org/10.1038/nri3531 CrossRefGoogle Scholar
  23. 23.
    Somanchi SS, Kennis BA, Gopalakrishnan V, Lee DA, Bankson JA (2016) In vivo (19)F-magnetic resonance imaging of adoptively transferred NK cells. Methods Mol Biol 1441:317–332.  https://doi.org/10.1007/978-1-4939-3684-7_27 CrossRefGoogle Scholar
  24. 24.
    Lim YT, Cho MY, Kang JH, Noh YW, Cho JH, Hong KS, Chung JW, Chung BH (2010) Perfluorodecalin/[InGaP/ZnS quantum dots] nanoemulsions as 19F MR/optical imaging nanoprobes for the labeling of phagocytic and nonphagocytic immune cells. Biomaterials 31:4964–4971.  https://doi.org/10.1016/j.biomaterials.2010.02.065 CrossRefGoogle Scholar
  25. 25.
    Lichtenfels R, Biddison WE, Schulz H, Vogt AB, Martin R (1994) CARE-LASS (calcein-release-assay), an improved fluorescence-based test system to measure cytotoxic T lymphocyte activity. J Immunol Methods 172:227–239CrossRefGoogle Scholar
  26. 26.
    Cholujova D, Jakubikova J, Kubes M, Arendacka B, Sapak M, Ihnatko R, Sedlak J (2008) Comparative study of four fluorescent probes for evaluation of natural killer cell cytotoxicity assays. Immunobiology 213:629–640.  https://doi.org/10.1016/j.imbio.2008.02.006 CrossRefGoogle Scholar
  27. 27.
    Kelly WJ, Shah NJ, Subramaniam DS (2018) Management of brain metastases in epidermal growth factor receptor mutant non-small-cell lung cancer. Front Oncol 8:208.  https://doi.org/10.3389/fonc.2018.00208 CrossRefGoogle Scholar
  28. 28.
    Lauko A, Thapa B, Venur VA, Ahluwalia MS (2018) Management of brain metastases in the new era of checkpoint inhibition. Curr Neurol Neurosci Rep 18:70.  https://doi.org/10.1007/s11910-018-0877-8 CrossRefGoogle Scholar
  29. 29.
    Kwon HJ, Kim N, Kim HS (2017) Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy. Exp Mol Med 49:e311.  https://doi.org/10.1038/emm.2017.42 CrossRefGoogle Scholar
  30. 30.
    Seo H, Kim BS, Bae EA, Min BS, Han YD, Shin SJ, Kang CY (2018) IL21 therapy combined with PD-1 and Tim-3 blockade provides enhanced NK cell antitumor activity against MHC class I-deficient tumors. Cancer Immunol Res 6:685–695.  https://doi.org/10.1158/2326-6066.CIR-17-0708 CrossRefGoogle Scholar
  31. 31.
    Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273CrossRefGoogle Scholar
  32. 32.
    Chang TC, Carter RA, Li Y, Li Y, Wang H, Edmonson MN, Chen X, Arnold P, Geiger TL, Wu G, Peng J, Dyer M, Downing JR, Green DR, Thomas PG, Zhang J (2017) The neoepitope landscape in pediatric cancers. Genome Med 9:78.  https://doi.org/10.1186/s13073-017-0468-3 CrossRefGoogle Scholar
  33. 33.
    Knorr DA, Bachanova V, Verneris MR, Miller JS (2014) Clinical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol 26:161–172.  https://doi.org/10.1016/j.smim.2014.02.002 CrossRefGoogle Scholar
  34. 34.
    Granzin M, Wagner J, Kohl U, Cerwenka A, Huppert V, Ullrich E (2017) Shaping of natural killer cell antitumor activity by ex vivo cultivation. Front Immunol 8:458.  https://doi.org/10.3389/fimmu.2017.00458 CrossRefGoogle Scholar
  35. 35.
    Veluchamy JP, Kok N, van der Vliet HJ, Verheul HMW, de Gruijl TD, Spanholtz J (2017) The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: recent innovations and future developments. Front Immunol 8:631.  https://doi.org/10.3389/fimmu.2017.00631 CrossRefGoogle Scholar
  36. 36.
    Gieryng A, Pszczolkowska D, Walentynowicz KA, Rajan WD, Kaminska B (2017) Immune microenvironment of gliomas. Lab Invest 97:498–518.  https://doi.org/10.1038/labinvest.2017.19 CrossRefGoogle Scholar
  37. 37.
    Sherman H, Gitschier HJ, Rossi AE (2018) A novel three-dimensional immune oncology model for high-throughput testing of tumoricidal activity. Front Immunol 9:857.  https://doi.org/10.3389/fimmu.2018.00857 CrossRefGoogle Scholar
  38. 38.
    Uong TNT, Lee KH, Ahn SJ, Kim KW, Min JJ, Hyun H, Yoon MS (2018) Real-time tracking of ex vivo-expanded natural killer cells toward human triple-negative breast cancers. Front Immunol 9:825.  https://doi.org/10.3389/fimmu.2018.00825 CrossRefGoogle Scholar
  39. 39.
    Waiczies S, Niendorf T, Lombardi G (2017) Labeling of cell therapies: how can we get it right? Oncoimmunology 6:e1345403.  https://doi.org/10.1080/2162402X.2017.1345403 CrossRefGoogle Scholar
  40. 40.
    Nabekura T, Lanier LL (2016) Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection. J Exp Med 213:2745–2758.  https://doi.org/10.1084/jem.20160726 CrossRefGoogle Scholar
  41. 41.
    Srinivas M, Heerschap A, Ahrens ET, Figdor CG, de Vries IJ (2010) (19)F MRI for quantitative in vivo cell tracking. Trends Biotechnol 28:363–370.  https://doi.org/10.1016/j.tibtech.2010.04.002 CrossRefGoogle Scholar
  42. 42.
    Helfer BM, Balducci A, Nelson AD, Janjic JM, Gil RR, Kalinski P, de Vries IJ, Ahrens ET, Mailliard RB (2010) Functional assessment of human dendritic cells labeled for in vivo (19)F magnetic resonance imaging cell tracking. Cytotherapy 12:238–250.  https://doi.org/10.3109/14653240903446902 CrossRefGoogle Scholar
  43. 43.
    Srinivas M, Boehm-Sturm P, Figdor CG, de Vries IJ, Hoehn M (2012) Labeling cells for in vivo tracking using (19)F MRI. Biomaterials 33:8830–8840.  https://doi.org/10.1016/j.biomaterials.2012.08.048 CrossRefGoogle Scholar
  44. 44.
    Ahrens ET, Helfer BM, O’Hanlon CF, Schirda C (2014) Clinical cell therapy imaging using a perfluorocarbon tracer and fluorine-19 MRI. Magn Reson Med 72:1696–1701.  https://doi.org/10.1002/mrm.25454 CrossRefGoogle Scholar
  45. 45.
    Kodibagkar VD, Wang X, Mason RP (2008) Physical principles of quantitative nuclear magnetic resonance oximetry. Front Biosci 13:1371–1384CrossRefGoogle Scholar
  46. 46.
    Einstein SA, Weegman BP, Firpo MT, Papas KK, Garwood M (2016) Development and validation of noninvasive magnetic resonance relaxometry for the in vivo assessment of tissue-engineered graft oxygenation. Tissue Eng Part C 22:1009–1017.  https://doi.org/10.1089/ten.TEC.2016.0106 CrossRefGoogle Scholar
  47. 47.
    Janjic JM, Srinivas M, Kadayakkara DK, Ahrens ET (2008) Self-delivering nanoemulsions for dual fluorine-19 MRI and fluorescence detection. J Am Chem Soc 130:2832–2841.  https://doi.org/10.1021/ja077388j CrossRefGoogle Scholar
  48. 48.
    Ahrens ET, Flores R, Xu H, Morel PA (2005) In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol 23:983–987.  https://doi.org/10.1038/nbt1121 CrossRefGoogle Scholar
  49. 49.
    Fink C, Gaudet JM, Fox MS, Bhatt S, Viswanathan S, Smith M, Chin J, Foster PJ, Dekaban GA (2018) (19)F-perfluorocarbon-labeled human peripheral blood mononuclear cells can be detected in vivo using clinical MRI parameters in a therapeutic cell setting. Sci Rep 8:590.  https://doi.org/10.1038/s41598-017-19031-0 CrossRefGoogle Scholar
  50. 50.
    Gaudet JM, Ribot EJ, Chen Y, Gilbert KM, Foster PJ (2015) Tracking the fate of stem cell implants with fluorine-19 MRI. PLoS ONE 10:e0118544.  https://doi.org/10.1371/journal.pone.0118544 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019
Corrected Publication 2019

Authors and Affiliations

  • Bridget A. Kennis
    • 1
  • Keith A. Michel
    • 2
  • William B. Brugmann
    • 1
  • Alvaro Laureano
    • 1
    • 4
  • Rong-Hua Tao
    • 1
  • Srinivas S. Somanchi
    • 1
  • Samuel A. Einstein
    • 2
  • Javiera B. Bravo-Alegria
    • 1
  • Shinji Maegawa
    • 1
  • Andrew Wahba
    • 1
  • Simin Kiany
    • 1
  • Nancy Gordon
    • 1
  • Lucia Silla
    • 4
  • Dawid Schellingerhout
    • 3
  • Soumen Khatua
    • 1
  • Wafik Zaky
    • 1
  • David Sandberg
    • 1
    • 6
  • Laurence Cooper
    • 1
    • 5
  • Dean A. Lee
    • 1
    • 7
    Email author
  • James A. Bankson
    • 2
    • 9
    Email author
  • Vidya Gopalakrishnan
    • 1
    • 8
    Email author
  1. 1.Division of PediatricsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Imaging PhysicsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Diagnostic RadiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Division of Transplantation and Cellular Therapy, Hospital das Clinicas de Porto AlegreFederal University of Rio Grande do SulPorto AlegreBrazil
  5. 5.Ziopharm OncologyBostonUSA
  6. 6.Department of Pediatric NeurosurgeryUniversity of Texas Health Science CenterHoustonUSA
  7. 7.Department of PediatricsOhio State UniversityColumbusUSA
  8. 8.Division of PediatricsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  9. 9.Department of Imaging PhysicsThe University of Texas MD Anderson Cancer CenterHoustonUSA

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