Abstract
Purpose
Tumor immunotherapy has the advantages of high specificity, minimal damage to the patient’s body, and a long-lasting anti-tumor effect. However, due to the existence of immune escape phenomenon, the effect of anti-tumor immunotherapy is still poor. Therefore, a cancer vaccine that reverses tumor-associated immunosuppression is a very promising approach for research and treatment.
Methods
Vaccines were prepared using autologous and allogeneic tumor cells and their lysates to syngeneic tumor cell lysates as immunogens. The glioma cell proliferation, apoptosis and the secretion level of MCP-2, IFN-γ were detected to evaluate the efficacy of this treatment against glioma in vitro. In addition, a rat glioma model was established to investigate the anti-tumor effect in vivo, and evaluated its efficacy by observing the changes of CD4 + T cells, CD8 + T cells, NK cells, and the level of IL-2 and IL-10 in peripheral blood before and after treatment.
Results
The C6 + 9L glioma cell lysate vaccine (C6 + 9L-CL) not only inhibited the proliferation of glioma cells and promoted their apoptosis in vitro, but also significantly inhibited the tumor growth in vivo and improved the survival time of rats. In addition, the C6 + 9L-CL vaccine enhanced the anti-tumor immune response by promoting the secretion of T cell chemokines MCP-2, IFN-γ and IL-2, and by stimulating the proliferation of T cells and NK cells in peripheral blood and glioma tissues.
Conclusion
Our findings demonstrate the inhibitory effect of molecular mimic vaccines on glioma and provided a theoretical basis for molecular mimic hybrid vaccines as a potential therapeutic approach.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Abedelahi A, Hasanzadeh H, Hadizadeh H, Joghataie MT (2013) Morphometric and volumetric study of caudate and putamen nuclei in normal individuals by MRI: effect of normal aging, gender and hemispheric differences. Pol J Radiol 78:7–14. https://doi.org/10.12659/pjr.889364
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772. https://doi.org/10.1093/intimm/8.5.765
Allen SJ, Mott KR, Chentoufi AA, BenMohamed L, Wechsler SL, Ballantyne CM, Ghiasi H (2011) CD11c controls herpes simplex virus 1 responses to limit virus replication during primary infection. J Virol 85:9945–9955. https://doi.org/10.1128/jvi.05208-11
Altmann DM (2018) A Nobel Prize-worthy pursuit: cancer immunology and harnessing immunity to tumour neoantigens. Immunology 155:283–284. https://doi.org/10.1111/imm.13008
Baumann CA, Badamchian M, Goldstein AL (2000) Thymosin alpha1 is a time and dose-dependent antagonist of dexamethasone-induced apoptosis of murine thymocytes in vitro. Int J Immunopharmacol 22:1057–1066. https://doi.org/10.1016/s0192-0561(00)00065-5
Beutler AS, Banck MS, Wedekind D, Hedrich HJ (1999) Tumor gene therapy made easy: allogeneic major histocompatibility complex in the C6 rat glioma model. Hum Gene Ther 10:95–101. https://doi.org/10.1089/10430349950019228
Boehm U, Klamp T, Groot M, Howard JC (1997) Cellular responses to interferon-gamma. Annu Rev Immunol 15:749–795. https://doi.org/10.1146/annurev.immunol.15.1.749
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. https://doi.org/10.1056/NEJMoa1200694
Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A, Priceman SJ, Wang X, Harshbarger TL, D’Apuzzo M, Ressler JA, Jensen MC, Barish ME, Chen M, Portnow J, Forman SJ, Badie B (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 375:2561–2569. https://doi.org/10.1056/NEJMoa1610497
Colonna M, Pulendran B, Iwasaki A (2006) Dendritic cells at the host-pathogen interface. Nat Immunol 7:117–120. https://doi.org/10.1038/ni0206-117
Cresswell P (1994) Assembly, transport, and function of MHC class II molecules. Annu Rev Immunol 12:259–293. https://doi.org/10.1146/annurev.iy.12.040194.001355
Curnis F, Gasparri A, Sacchi A, Cattaneo A, Magni F, Corti A (2005) Targeted delivery of IFNgamma to tumor vessels uncouples antitumor from counterregulatory mechanisms. Cancer Res 65:2906–2913. https://doi.org/10.1158/0008-5472.Can-04-4282
Farrar MA, Schreiber RD (1993) The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol 11:571–611. https://doi.org/10.1146/annurev.iy.11.040193.003035
Gardner A, Ruffell B (2016) Dendritic cells and cancer immunity. Trends Immunol 37:855–865. https://doi.org/10.1016/j.it.2016.09.006
Gardner TA, Elzey BD, Hahn NM (2012) Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. Hum Vaccin Immunother 8:534–539. https://doi.org/10.4161/hv.19795
Goldstein AL, Low TL, McAdoo M, McClure J, Thurman GB, Rossio J, Lai CY, Chang D, Wang SS, Harvey C, Ramel AH, Meienhofer J (1977) Thymosin alpha1: isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci U S A 74:725–729. https://doi.org/10.1073/pnas.74.2.725
Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 155:1823–1841. https://doi.org/10.1084/jem.155.6.1823
Hu B, Wei YQ (2004) Molecular mimicry associated with infection, autoimmunity, and tumor immunotherapy. Chin Bull Life Sci 16:66–72
Iorgulescu JB, Braun D, Oliveira G, Keskin DB, Wu CJ (2018) Acquired mechanisms of immune escape in cancer following immunotherapy. Genome Med 10:87. https://doi.org/10.1186/s13073-018-0598-2
Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895
Jäger D, Jäger E, Knuth A (2001) Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer. J Clin Pathol 54:669–674. https://doi.org/10.1136/jcp.54.9.669
Jia Z, Feng Z, Tian R, Wang Q, Wang L (2015) Thymosin α1 plus routine treatment inhibit inflammatory reaction and improve the quality of life in AECOPD patients. Immunopharmacol Immunotoxicol 37:388–392. https://doi.org/10.3109/08923973.2015.1069837
Johansen A, Christensen SJ, Scheie D, Højgaard JLS, Kondziella D (2019) Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: systematic review. Neurology 92:663–674. https://doi.org/10.1212/wnl.0000000000007235
Lalvani A, Millington KA (2008) T-cell interferon-gamma release assays: can we do better? Eur Respir J 32:1428–1430. https://doi.org/10.1183/09031936.00148308
Li XL, Zeng S, He HP, Zeng X, Peng LL, Chen LG (2020) A hybrid glioma tumor cell lysate immunotherapy vaccine demonstrates good clinical efficacy in the rat model. Onco Targets Ther 13:8109–8124. https://doi.org/10.2147/ott.S259516
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341. https://doi.org/10.1038/nature14432
Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y (2015) The paradoxical role of IL-10 in immunity and cancer. Cancer Lett 367:103–107. https://doi.org/10.1016/j.canlet.2015.07.009
Maverakis E, van den Elzen P, Sercarz EE (2001) Self-reactive T cells and degeneracy of T cell recognition: evolving concepts-from sequence homology to shape mimicry and TCR flexibility. J Autoimmun 16:201–209. https://doi.org/10.1006/jaut.2000.0493
Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258. https://doi.org/10.1016/s0092-8674(01)00449-4
Miller AM, DeAngelis LM (2020) Reevaluation of the frequent use of PD-1 checkpoint inhibitors for treatment of glioblastoma. JAMA 323:2482–2484. https://doi.org/10.1001/jama.2020.5934
Morgan DA, Ruscetti FW, Gallo R (1976) Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193:1007–1008. https://doi.org/10.1126/science.181845
N’Diaye M, Warnecke A, Flytzani S, Abdelmagid N, Ruhrmann S, Olsson T, Jagodic M, Harris RA, Guerreiro-Cacais AO (2016) Rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3L exhibit distinct phenotypical and functional characteristics. J Leukoc Biol 99:437–446. https://doi.org/10.1189/jlb.1AB0914-433RR
Ni C, Wu P, Wu X, Zhang T, Zhang T, Wang Z, Zhang S, Qiu F, Huang J (2015) Thymosin alpha1 enhanced cytotoxicity of iNKT cells against colon cancer via upregulating CD1d expression. Cancer Lett 356:579–588. https://doi.org/10.1016/j.canlet.2014.10.002
Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, Mintz AH, Engh JA, Bartlett DL, Brown CK, Zeh H, Holtzman MP, Reinhart TA, Whiteside TL, Butterfield LH, Hamilton RL, Potter DM, Pollack IF, Salazar AM, Lieberman FS (2011) Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol 29:330–336. https://doi.org/10.1200/jco.2010.30.7744
Ouyang W, O’Garra A (2019) IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity 50:871–891. https://doi.org/10.1016/j.immuni.2019.03.020
Paley PJ, Veljovich DS, Shah CA, Everett EN, Bondurant AE, Drescher CW, Peters WA 3rd (2011) Surgical outcomes in gynecologic oncology in the era of robotics: analysis of first 1000 cases. Am J Obstet Gynecol 204:551.e551-559. https://doi.org/10.1016/j.ajog.2011.01.059
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW (2015) Phase I study of pembrolizumab (MK-3475; Anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 21:4286–4293. https://doi.org/10.1158/1078-0432.Ccr-14-2607
Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168. https://doi.org/10.1056/NEJMra1703481
Pulendran B, Tang H, Denning TL (2008) Division of labor, plasticity, and crosstalk between dendritic cell subsets. Curr Opin Immunol 20:61–67. https://doi.org/10.1016/j.coi.2007.10.009
Ramachandran M, Dimberg A, Essand M (2017) The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells. Semin Cancer Biol 45:23–35. https://doi.org/10.1016/j.semcancer.2017.02.010
Siegel JP, Sharon M, Smith PL, Leonard WJ (1987) The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science 238:75–78. https://doi.org/10.1126/science.3116668
Sioud M (2002) How does autoimmunity cause tumor regression? A potential mechanism involving cross-reaction through epitope mimicry. Mol Med 8:115–119
Stathopoulos A, Samuelson C, Milbouw G, Hermanne JP, Schijns VE, Chen TC (2008) Therapeutic vaccination against malignant gliomas based on allorecognition and syngeneic tumor antigens: proof of principle in two strains of rat. Vaccine 26:1764–1772. https://doi.org/10.1016/j.vaccine.2008.01.039
Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M (2020) Management of glioblastoma: state of the art and future directions. CA Cancer J Clin 70:299–312. https://doi.org/10.3322/caac.21613
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690
Wang H, Su X, Zhang P, Liang J, Wei H, Wan M, Wu X, Yu Y, Wang L (2011) Recombinant heat shock protein 65 carrying PADRE and HBV epitopes activates dendritic cells and elicits HBV-specific CTL responses. Vaccine 29:2328–2335. https://doi.org/10.1016/j.vaccine.2010.12.124
Yan Y, Zeng S, Gong Z, Xu Z (2020) Clinical implication of cellular vaccine in glioma: current advances and future prospects. J Exp Clin Cancer Res 39:257. https://doi.org/10.1186/s13046-020-01778-6
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We thank Medjaden Inc. for scientific editing of this manuscript.
Funding
This work was supported by the Science and Technology Department of Sichuan Province [No. 2018JY0404]; Luzhou Municipal People’s Government [No. 2020-SYF-28; No. 2020-JYJ-20].
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Conceptualization: LP and LC; data curation: HH, YC and XZ; formal analysis: HH, YC and PW; funding acquisition: LP, LC and CZ; investigation: HH, XZ, SZ, XL and XL; methodology: CZ and YM; project administration: LP; supervision: LP and LC; roles/writing—original draft: HH, YC and PW; writing—review and editing: LP and LC.
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He, H., Cen, Y., Wang, P. et al. The therapeutic effect of an autologous and allogenic mixed glioma cell lysate vaccine in a rat model. J Cancer Res Clin Oncol 149, 609–622 (2023). https://doi.org/10.1007/s00432-022-04281-x
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DOI: https://doi.org/10.1007/s00432-022-04281-x