Clinically relevant immune responses against cytomegalovirus: Implications for precision medicine

International Journal of Molecular Sciences

Volumn 20, Issue 8, 2019, Pages

  Lérias, Joana R ^a   Paraschoudi, Georgia ^a   Silva, Inês ^a   Martins, João ^a   de Sousa, Eric ^a   Condeço, Carolina ^a   Figueiredo, Nuno ^a   Carvalho, Carlos ^a   Dodoo, Ernest ^b   Jäger, Elke ^b   Rao, Martin ^a   Maeurer, Markus ^a,b  

^a CHAMPALIMAUD CENTRE FOR THE UNKNOWN   (Portugal)

^b KRANKENHAUS NORDWEST   (Germany)

Author keywords

Antibodies; Cancer; Cytomegalovirus; Immune responses; Immunotherapy; Interferon gamma; T cells

Indexed keywords

CYTOMEGALOVIRUS ANTIGEN PP65; EPITOPE; GAMMA INTERFERON; PHYTOHEMAGGLUTININ; TUMOR NECROSIS FACTOR;

ANTINEOPLASTIC ACTIVITY; BASAL CELL CARCINOMA; CANCER IMMUNOTHERAPY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL CULTURE; CELL EXPANSION; CELL INFILTRATION; CELL INVASION; CELLULAR IMMUNITY; COLORECTAL CANCER; CUTANEOUS MELANOMA; CYTOMEGALOVIRUS; CYTOTOXIC T LYMPHOCYTE; ENZYME LINKED IMMUNOSORBENT ASSAY; ESOPHAGUS CANCER; HUMAN; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOREACTIVITY; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOTHERAPY; INFLAMMATION; PERIPHERAL BLOOD MONONUCLEAR CELL; PERITONEUM METASTASIS; PERSONALIZED MEDICINE; PLANT TISSUE CULTURE; REVIEW; RNA SEQUENCE; T LYMPHOCYTE ACTIVATION; TUMOR ASSOCIATED LEUKOCYTE; TUMOR CELL; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; TUMOR REJECTION; UPREGULATION; VIRUS INFECTION; ANIMAL; COMPLICATION; CYTOMEGALOVIRUS INFECTION; IMMUNITY; IMMUNOLOGY; NEOPLASM; PROCEDURES; VIROLOGY;

ANIMALS; CYTOMEGALOVIRUS; CYTOMEGALOVIRUS INFECTIONS; HUMANS; IMMUNITY; IMMUNOTHERAPY; NEOPLASMS; PRECISION MEDICINE;

EID: 85065298892     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms20081986     Document Type: Review

References (67)

1. Souquette, A.; Frere, J.; Smithey, M.; Sauce, D.; Thomas, P.G. A constant companion: Immune recognition and response to cytomegalovirus with aging and implications for immune fitness. GeroScience 2017, 39, 293–303. [CrossRef]
2. Kotton, C.N.; Kumar, D.; Caliendo, A.M.; Huprikar, S.; Chou, S.; Danziger-Isakov, L.; Humar, A. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2018, 102, 900–931. [CrossRef] [PubMed]
3. Chen, K.; Cheng, M.P.; Hammond, S.P.; Einsele, H.; Marty, F.M. Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation. Blood Adv. 2018, 2, 2159–2175. [CrossRef] [PubMed]
4. Fowler, K.B.; Boppana, S.B. Congenital cytomegalovirus infection. Semin. Perinatol. 2018, 42, 149–154. [CrossRef]
5. Adland, E.; Klenerman, P.; Goulder, P.; Matthews, P.C. Ongoing burden of disease and mortality from HIV/CMV coinfection in Africa in the antiretroviral therapy era. Front. Microbiol. 2015, 6, 1016. [CrossRef] [PubMed]
6. Sehrawat, S.; Kumar, D.; Rouse, B.T. Herpesviruses: Harmonious Pathogens but Relevant Cofactors in Other Diseases? Front. Cell. Infect. Microbiol. 2018, 8. [CrossRef] [PubMed]
7. La Rosa, C.; Diamond, D.J. The immune response to human CMV. Future Virol. 2012, 7, 279–293. [CrossRef]
8. Muccio, L.; Bertaina, A.; Falco, M.; Pende, D.; Meazza, R.; Lopez-Botet, M.; Moretta, L.; Locatelli, F.; Moretta, A.; Della Chiesa, M. Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies. Haematologica 2016, 101, 371–381. [CrossRef]
9. Iancu, E.M.; Corthesy, P.; Baumgaertner, P.; Devevre, E.; Voelter, V.; Romero, P.; Speiser, D.E.; Rufer, N. Clonotype selection and composition of human CD8 T cells specific for persistent herpes viruses varies with differentiation but is stable over time. J. Immunol. 2009, 183, 319–331. [CrossRef] [PubMed]
10. Okhrimenko, A.; Grun, J.R.; Westendorf, K.; Fang, Z.; Reinke, S.; von Roth, P.; Wassilew, G.; Kuhl, A.A.; Kudernatsch, R.; Demski, S.; et al. Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory. Proc. Natl. Acad. Sci. USA 2014, 111, 9229–9234. [CrossRef] [PubMed]
11. Turula, H.; Smith, C.J.; Grey, F.; Zurbach, K.A.; Snyder, C.M. Competition between T cells maintains clonal dominance during memory inflation induced by MCMV. Eur. J. Immunol. 2013, 43, 1252–1263. [CrossRef]
12. Wang, G.C.; Dash, P.; McCullers, J.A.; Doherty, P.C.; Thomas, P.G. T cell receptor alphabeta diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection. Sci. Transl. Med. 2012, 4, 128ra142. [CrossRef]
13. Huth, A.; Liang, X.; Krebs, S.; Blum, H.; Moosmann, A. Antigen-Specific TCR Signatures of Cytomegalovirus Infection. J. Immunol. 2019, 202, 979–990. [CrossRef]
14. van de Berg, P.J.; Heutinck, K.M.; Raabe, R.; Minnee, R.C.; Young, S.L.; van Donselaar van der Pant, K.A.; Bemelman, F.J.; van Lier, R.A.; ten Berge, I.J. Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature. J. Infect. Dis. 2010, 202, 690–699. [CrossRef]
15. Turner, J.E.; Campbell, J.P.; Edwards, K.M.; Howarth, L.J.; Pawelec, G.; Aldred, S.; Moss, P.; Drayson, M.T.; Burns, V.E.; Bosch, J.A. Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults. Age 2014, 36, 287–297. [CrossRef]
16. Di Benedetto, S.; Gaetjen, M.; Müller, L. The Modulatory Effect of Gender and Cytomegalovirus-Seropositivity on Circulating Inflammatory Factors and Cognitive Performance in Elderly Individuals. Int. J. Mol. Sci. 2019, 20, 990. [CrossRef]
17. Liu, Z.; Poiret, T.; Meng, Q.; Rao, M.; von Landenberg, A.; Schoutrop, E.; Valentini, D.; Dodoo, E.; Peredo-Harvey, I.; Maeurer, M. Epstein-Barr virus-and cytomegalovirus-specific immune response in patients with brain cancer. J. Transl. Med. 2018, 16, 182. [CrossRef]
18. Nagu, T.; Aboud, S.; Rao, M.; Matee, M.; Axelsson, R.; Valentini, D.; Mugusi, F.; Zumla, A.; Maeurer, M. Strong anti-Epstein Barr virus (EBV) or cytomegalovirus (CMV) cellular immune responses predict survival and a favourable response to anti-tuberculosis therapy. Int. J. Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis. 2017, 56, 136–139. [CrossRef]
19. Rahbar, A.; Peredo, I.; Solberg, N.W.; Taher, C.; Dzabic, M.; Xu, X.; Skarman, P.; Fornara, O.; Tammik, C.; Yaiw, K.; et al. Discordant humoral and cellular immune responses to Cytomegalovirus (CMV) in glioblastoma patients whose tumors are positive for CMV. Oncoimmunology 2015, 4, e982391. [CrossRef]
20. Mitchell, D.A.; Xie, W.; Schmittling, R.; Learn, C.; Friedman, A.; McLendon, R.E.; Sampson, J.H. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro-Oncology 2008, 10, 10–18. [CrossRef]
21. Priel, E.; Wohl, A.; Teperberg, M.; Nass, D.; Cohen, Z.R. Human cytomegalovirus viral load in tumor and peripheral blood samples of patients with malignant gliomas. J. Clin. Neurosci. Off. J. Neurosurg. Soc. Australas 2015, 22, 326–330. [CrossRef]
22. Stragliotto, G.; Rahbar, A.; Solberg, N.W.; Lilja, A.; Taher, C.; Orrego, A.; Bjurman, B.; Tammik, C.; Skarman, P.; Peredo, I.; et al. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: A randomized, double-blind, hypothesis-generating study. Int. J. Cancer 2013, 133, 1204–1213. [CrossRef]
23. Söderberg-Nauclér, C.; Rahbar, A.; Stragliotto, G. Survival in patients with glioblastoma receiving valganciclovir. N. Engl. J. Med. 2013, 369, 985–986. [CrossRef]
24. Solomon, I.H.; Ramkissoon, S.H.; Milner, D.A., Jr.; Folkerth, R.D. Cytomegalovirus and glioblastoma: A review of evidence for their association and indications for testing and treatment. J. Neuropathol. Exp. Neurol. 2014, 73, 994–998. [CrossRef]
25. Nair, S.K.; De Leon, G.; Boczkowski, D.; Schmittling, R.; Xie, W.; Staats, J.; Liu, R.; Johnson, L.A.; Weinhold, K.; Archer, G.E.; et al. Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2014, 20, 2684–2694. [CrossRef]
26. Crough, T.; Beagley, L.; Smith, C.; Jones, L.; Walker, D.G.; Khanna, R. Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme. Immunol. Cell Biol. 2012, 90, 872–880. [CrossRef]
27. Xing, Y.; Wang, Y.; Wang, S.; Wang, X.; Fan, D.; Zhou, D.; An, J. Human cytomegalovirus infection contributes to glioma disease progression via upregulating endocan expression. Transl. Res. J. Lab. Clin. Med. 2016, 177, 113–126. [CrossRef]
28. Cobbs, C.S.; Soroceanu, L.; Denham, S.; Zhang, W.; Britt, W.J.; Pieper, R.; Kraus, M.H. Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness. J. Neuro-Oncol. 2007, 85, 271–280. [CrossRef]
29. Bai, B.; Wang, X.; Chen, E.; Zhu, H. Human cytomegalovirus infection and colorectal cancer risk: A meta-analysis. Oncotarget 2016, 7, 76735–76742. [CrossRef]
30. Herbein, G.; Kumar, A. The oncogenic potential of human cytomegalovirus and breast cancer. Front. Oncol. 2014, 4, 230. [CrossRef]
31. Franklin, C.; Rooms, I.; Fiedler, M.; Reis, H.; Milsch, L.; Herz, S.; Livingstone, E.; Zimmer, L.; Schmid, K.W.; Dittmer, U.; et al. Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis. Eur. J. Cancer 2017, 86, 248–256. [CrossRef]
32. Lankes, K.; Hundorfean, G.; Harrer, T.; Pommer, A.J.; Agaimy, A.; Angelovska, I.; Tajmir-Riahi, A.; Gohl, J.; Schuler, G.; Neurath, M.F.; et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis. Oncoimmunology 2016, 5, e1128611. [CrossRef]
33. Schulz, U.; Solidoro, P.; Müller, V.; Szabo, A.; Gottlieb, J.; Wilkens, H.; Enseleit, F. CMV Immunoglobulins for the Treatment of CMV Infections in Thoracic Transplant Recipients. Transplantation 2016, 100, S5–S10. [CrossRef]
34. Schampera, M.S.; Schweinzer, K.; Abele, H.; Kagan, K.O.; Klein, R.; Rettig, I.; Jahn, G.; Hamprecht, K. Comparison of cytomegalovirus (CMV)-specific neutralization capacity of hyperimmunoglobulin (HIG) versus standard intravenous immunoglobulin (IVIG) preparations: Impact of CMV IgG normalization. J. Clin. Virol. Off. Publ. Pan Am. Soc. Clin. Virol. 2017, 90, 40–45. [CrossRef]
35. Alsuliman, T.; Kitel, C.; Dulery, R.; Guillaume, T.; Larosa, F.; Cornillon, J.; Labussiere-Wallet, H.; Mediavilla, C.; Belaiche, S.; Delage, J.; et al. Cytotect(R)CP as salvage therapy in patients with CMV infection following allogeneic hematopoietic cell transplantation: A multicenter retrospective study. Bone Marrow Transplant. 2018, 53, 1328–1335. [CrossRef]
36. Tan, B.H. Cytomegalovirus Treatment. Curr. Treat. Options Infect. Dis. 2014, 6, 256–270. [CrossRef]
37. Meng, Q.; Valentini, D.; Rao, M.; Dodoo, E.; Maeurer, M. CMV and EBV targets recognized by tumor-infiltrating B lymphocytes in pancreatic cancer and brain tumors. Sci. Rep. 2018, 8, 17079–17089. [CrossRef]
38. Scheper, W.; van Dorp, S.; Kersting, S.; Pietersma, F.; Lindemans, C.; Hol, S.; Heijhuurs, S.; Sebestyen, Z.; Gründer, C.; Marcu-Malina, V. γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia. Leukemia 2013, 27, 1328–1338. [CrossRef]
39. Pfirrmann, V.; Oelsner, S.; Rettinger, E.; Huenecke, S.; Bonig, H.; Merker, M.; Wels, W.S.; Cinatl, J.; Schubert, R.; Klingebiel, T.; et al. Cytomegalovirus-specific cytokine-induced killer cells: Concurrent targeting of leukemia and cytomegalovirus. Cytotherapy 2015, 17, 1139–1151. [CrossRef]
40. Lee, M.; Park, C.; Woo, J.; Kim, J.; Kho, I.; Nam, D.-H.; Park, W.-Y.; Kim, Y.-S.; Kong, D.-S.; Lee, H.W.; et al. Preferential Infiltration of Unique Vγ9Jγ2-Vδ2 T Cells Into Glioblastoma Multiforme. Front. Immunol. 2019, 10. [CrossRef]
41. Chen, G.; Yang, X.; Ko, A.; Sun, X.; Gao, M.; Zhang, Y.; Shi, A.; Mariuzza, R.A.; Weng, N.P. Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8(+) TCR Repertoires to Immunodominant Viral Antigens. Cell Rep. 2017, 19, 569–583. [CrossRef]
42. Weile, J.; Streeck, B.; Muck, J.; Krebs, G.; Jakobus, K.-H.; Knabbe, C.; Weber, F. Severe cytomegalovirus-associated esophagitis in an immunocompetent patient after short-term steroid therapy. J. Clin. Microbiol. 2009, 47, 3031–3033. [CrossRef]
43. Chan, A.; Bazerbachi, F.; Hanson, B.; Alraies, M.C.; Duran-Nelson, A. Cytomegalovirus hepatitis and pancreatitis in the immunocompetent. Ochsner J. 2014, 14, 295–299.
44. Bedri, S.; Sultan, A.A.; Alkhalaf, M.; Al Moustafa, A.E.; Vranic, S. Epstein-Barr virus (EBV) status in colorectal cancer: A mini review. Hum. Vaccines Immunother. 2018. [CrossRef]
45. Erkes, D.A.; Smith, C.J.; Wilski, N.A.; Caldeira-Dantas, S.; Mohgbeli, T.; Snyder, C.M. Virus-Specific CD8+ T Cells Infiltrate Melanoma Lesions and Retain Function Independently of PD-1 Expression. J. Immunol. 2017. [CrossRef]
46. Bentz, G.L.; Yurochko, A.D. Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. Proc. Natl. Acad. Sci. USA 2008, 105, 5531–5536. [CrossRef]
47. Heiske, A.; Roettger, Y.; Bacher, M. Cytomegalovirus upregulates vascular endothelial growth factor and its second cellular kinase domain receptor in human fibroblasts. Viral Immunol. 2012, 25, 360–367. [CrossRef]
48. Muz, B.; de la Puente, P.; Azab, F.; Azab, A.K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 2015, 3, 83–92. [CrossRef]
49. Datta, M.; Via, L.E.; Kamoun, W.S.; Liu, C.; Chen, W.; Seano, G.; Weiner, D.M.; Schimel, D.; England, K.; Martin, J.D.; et al. Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery. Proc. Natl. Acad. Sci. USA 2015, 112, 1827–1832. [CrossRef]
50. Dong, H.; Qian, D.; Wang, Y.; Meng, L.; Chen, D.; Ji, X.; Feng, W. Survivin expression and serum levels in pancreatic cancer. World J. Surg. Oncol. 2015, 13, 189. [CrossRef]
51. Meng, Q.; Liu, Z.; Rangelova, E.; Poiret, T.; Ambati, A.; Rane, L.; Xie, S.; Verbeke, C.; Dodoo, E.; Del Chiaro, M.; et al. Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer. J. Immunother. 2016, 39, 81–89. [CrossRef]
52. Liu, Z.; Poiret, T.; Persson, O.; Meng, Q.; Rane, L.; Bartek, J., Jr.; Karbach, J.; Altmannsberger, H.M.; Illies, C.; Luo, X.; et al. NY-ESO-1-and survivin-specific T-cell responses in the peripheral blood from patients with glioma. Cancer Immunol. Immunother. CII 2018, 67, 237–246. [CrossRef]
53. Kim, J.; Kim, A.R.; Shin, E.C. Cytomegalovirus Infection and Memory T Cell Inflation. Immune Netw. 2015, 15, 186–190. [CrossRef] [PubMed]
54. Makler, O.; Oved, K.; Netzer, N.; Wolf, D.; Reiter, Y. Direct visualization of the dynamics of antigen presentation in human cells infected with cytomegalovirus revealed by antibodies mimicking TCR specificity. Eur. J. Immunol. 2010, 40, 1552–1565. [CrossRef]
55. Luo, X.H.; Meng, Q.; Rao, M.; Liu, Z.; Paraschoudi, G.; Dodoo, E.; Maeurer, M. The impact of inflationary cytomegalovirus-specific memory T cells on anti-tumour immune responses in patients with cancer. Immunology 2018, 155, 294–308. [CrossRef]
56. Antonioli, L.; Pacher, P.; Vizi, E.S.; Haskó, G. CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 2013, 19, 355–367. [CrossRef] [PubMed]
57. Simoni, Y.; Becht, E.; Fehlings, M.; Loh, C.Y.; Koo, S.L.; Teng, K.W.W.; Yeong, J.P.S.; Nahar, R.; Zhang, T.; Kared, H.; et al. Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018, 557, 575–579. [CrossRef]
58. Baumann, N.S.; Torti, N.; Welten, S.P.M.; Barnstorf, I.; Borsa, M.; Pallmer, K.; Oduro, J.D.; Cicin-Sain, L.; Ikuta, K.; Ludewig, B.; et al. Tissue maintenance of CMV-specific inflationary memory T cells by IL-15. PLoS Pathog. 2018, 14, e1006993. [CrossRef] [PubMed]
59. Waldmann, T.A. Interleukin-15 in the treatment of cancer. Expert Rev. Clin. Immunol. 2014, 10, 1689–1701. [CrossRef] [PubMed]
60. Hu, Q.; Ye, X.; Qu, X.; Cui, D.; Zhang, L.; Xu, Z.; Wan, H.; Zhang, L.; Tao, W. Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy. Sci. Rep. 2018, 8, 7675. [CrossRef] [PubMed]
61. Conlon, K.C.; Lugli, E.; Welles, H.C.; Rosenberg, S.A.; Fojo, A.T.; Morris, J.C.; Fleisher, T.A.; Dubois, S.P.; Perera, L.P.; Stewart, D.M.; et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015, 33, 74–82. [CrossRef] [PubMed]
62. Bahador, M.; Gras Navarro, A.; Rahman, M.A.; Dominguez-Valentin, M.; Sarowar, S.; Ulvestad, E.; Njolstad, G.; Lie, S.A.; Kristoffersen, E.K.; Bratland, E.; et al. Increased infiltration and tolerised antigen-specific CD8(+) TEM cells in tumor but not peripheral blood have no impact on survival of HCMV(+) glioblastoma patients. Oncoimmunology 2017, 6, e1336272. [CrossRef] [PubMed]
63. Prado-Garcia, H.; Romero-Garcia, S.; Puerto-Aquino, A.; Rumbo-Nava, U. The PD-L1/PD-1 pathway promotes dysfunction, but not “exhaustion”, in tumor-responding T cells from pleural effusions in lung cancer patients. Cancer Immunol. Immunother. CII 2017, 66, 765–776. [CrossRef] [PubMed]
64. Scheper, W.; Kelderman, S.; Fanchi, L.F.; Linnemann, C.; Bendle, G.; de Rooij, M.A.J.; Hirt, C.; Mezzadra, R.; Slagter, M.; Dijkstra, K.; et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 2019, 25, 89–94. [CrossRef] [PubMed]
65. Legut, M.; Dolton, G.; Mian, A.A.; Ottmann, O.G.; Sewell, A.K. CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. Blood 2018, 131, 311–322. [CrossRef]
66. Abken, H.; Wels, W.S.; Kühlcke, K. The Express Drivers: Chimeric Antigen Receptor-redirected T cells Make it to the Clinic. In Cancer Immunotherapy Meets Oncology: In Honor of Christoph Huber; Britten, C., Kreiter, S., Diken, M., Rammensee, H.-G., Eds.; Springers: Berlin/Heidelberg, Germany, 2014; p. 248.
67. Liu, Z.; Meng, Q.; Bartek, J.; Poiret, T.; Persson, O.; Rane, L.; Rangelova, E.; Illies, C.; Peredo, I.; Luo, X.; et al. Tumor-infiltrating T-cells (TIL) from patients with glioma. Oncoimmunology 2016, 6, e1252894. [CrossRef] [PubMed]