Skip to main content

Advertisement

Log in

Irradiated tumor cells of lipopolysaccharide stimulation elicit an enhanced anti-tumor immunity

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Lipopolysaccharide (LPS) is a major component of the outer surface membrane of Gram-negative bacteria which has been proved an effective immune enhancer. Here, we investigated the anti-tumor effect of irradiated tumor cells that stimulated by LPS in mouse xenografts models.

Methods

Tumor cells were irradiated after stimulation with 1 μg/mL LPS for 48 h. The C57BL/6 mice were immunized subcutaneously with irradiated tumor cells. The anti-tumor effect of lymphocytes of immunized mice was investigated. The cytotoxicity of spleen lymphocytes from immunized mice was determined by a standard 51Cr-release assay. The roles of immune cell subsets in anti-tumor activity were assessed by injected intraperitoneally with monoclonal antibodies.

Results

We observed that the vaccine of irradiated tumor cell with LPS-stimulated elicited a stronger protective anti-tumor immunity than other controls. Adoptive transfer of lymphocytes of immunized mice showed that the cellular immune response was involved in the anti-tumor effect. And this effect was achieved by activation of antigen-specific CD8+ T cell response and reduction of myeloid-derived suppressor cells (MDSCs, Gr1+ CD11b+), which were confirmed by depletion of immune cell subsets and flow cytometry analysis.

Conclusions

In summary, our study showed that stimulation of LPS was able to enhance anti-tumor immunity of vaccination with tumor cells after irradiation treatment, which might be a new strategy for cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Agarwalla P, Barnard Z, Fecci P, Dranoff G, Curry WT Jr (2012) Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J Immunother 35(5):385–389

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Andreani V, Gatti G, Simonella L, Rivero V, Maccioni M (2007) Activation of Toll-like receptor 4 on tumor cells in vitro inhibits subsequent tumor growth in vivo. Cancer Res 67(21):10519–10527

    Article  PubMed  CAS  Google Scholar 

  • Darveau RP, Chilton PM (2013) Naturally occurring low biological reactivity lipopolysaccharides as vaccine adjuvants. Expert Rev Vaccines 12(7):707–709

    Article  PubMed  CAS  Google Scholar 

  • Donaldson DM, Mitchell JR (1959) Immunization against Ehrlich’s ascites carcinoma with X-irradiated tumor cells. Proc Soc Exp Biol Med 101(2):204–207

    Article  PubMed  CAS  Google Scholar 

  • Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90(8):3539–3543

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, Bieler JG, Emens LA, Reilly RT, Jaffee EM (2005) Recruitment of latent pools of high-avidity CD8(+) T cells to the anti-tumor immune response. J Exp Med 201(10):1591–1602

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fioretti D, Iurescia S, Fazio VM, Rinaldi M (2010) DNA vaccines: developing new strategies against cancer. J Biomed Biotechnol 2010:174378

    Article  PubMed  PubMed Central  Google Scholar 

  • Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hodgkins SR, Ather JL, Paveglio SA, Allard JL, LeClair LA, Suratt BT, Boyson JE, Poynter ME (2010) NO2 inhalation induces maturation of pulmonary CD11c+ cells that promote antigen-specific CD4+ T cell polarization. Respir Res 11:102

    Article  PubMed  PubMed Central  Google Scholar 

  • Horton HM, Anderson D, Hernandez P, Barnhart KM, Norman JA, Parker SE (1999) A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon alpha. Proc Natl Acad Sci USA 96(4):1553–1558

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hu DE, Kettunen MI, Brindle KM (2005) Monitoring T-lymphocyte trafficking in tumors undergoing immune rejection. Magn Reson Med 54(6):1473–1479

    Article  PubMed  CAS  Google Scholar 

  • Hunn MK, Farrand KJ, Broadley KW, Weinkove R, Ferguson P, Miller RJ, Field CS, Petersen T, McConnell MJ, Hermans IF (2012) Vaccination with irradiated tumor cells pulsed with an adjuvant that stimulates NKT cells is an effective treatment for glioma. Clin Cancer Res 18(23):6446–6459

    Article  PubMed  CAS  Google Scholar 

  • Kabelitz D (2007) Expression and function of Toll-like receptors in T lymphocytes. Curr Opin Immunol 19(1):39–45

    Article  PubMed  CAS  Google Scholar 

  • Kacimi R, Giffard RG, Yenari MA (2011) Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappaB, JAK-STAT and JNK stress kinase pathways. J Inflamm (Lond) 8:7

    Article  CAS  Google Scholar 

  • Katsanis E, Bausero MA, Panoskaltsis-Mortari A, Dancisak BB, Xu Z, Orchard PJ, Davis CG, Blazar BR (1996) Irradiation of singly and doubly transduced murine neuroblastoma cells expressing B7-1 and producing interferon-gamma reduces their capacity to induce systemic immunity. Cancer Gene Ther 3(2):75–82

    PubMed  CAS  Google Scholar 

  • Keenan BP, Jaffee EM (2012) Whole cell vaccines—past progress and future strategies. Semin Oncol 39(3):276–286

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, Palmer DC, Antony PA, Hwang ST, Rosenberg SA, Waldmann TA, Restifo NP (2005) Central memory self/tumor-reactive CD8+ T cells confer superior anti-tumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 102(27):9571–9576

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kusmartsev SA, Li Y, Chen SH (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165(2):779–785

    Article  PubMed  CAS  Google Scholar 

  • Le DT, Pardoll DM, Jaffee EM (2010) Cellular vaccine approaches. Cancer J 16(4):304–310

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lin WN, Luo SF, Lee CW, Wang CC, Wang JS, Yang CM (2007) Involvement of MAPKs and NF-kappaB in LPS-induced VCAM-1 expression in human tracheal smooth muscle cells. Cell Signal 19(6):1258–1267

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Yang L, Cui Y, Wang X, Guo C, Huang Z, Kan Q, Liu Y (2009) Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm Bowel Dis 15(8):1133–1144

    Article  PubMed  Google Scholar 

  • Lu Y, Wei YQ, Tian L, Zhao X, Yang L, Hu B, Kan B, Wen YJ, Liu F, Deng HX, Li J, Mao YQ, Lei S, Huang MJ, Peng F, Jiang Y, Zhou H, Zhou LQ, Luo F (2003) Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor. J Immunol 170(6):3162–3170

    Article  PubMed  CAS  Google Scholar 

  • Mapara MY, Sykes M (2004) Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol 22(6):1136–1151

    Article  PubMed  CAS  Google Scholar 

  • Martin MD, Wirth TC, Lauer P, Harty JT, Badovinac VP (2011) The impact of pre-existing memory on differentiation of newly recruited naive CD8 T cells. J Immunol 187(6):2923–2931

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mauceri HJ, Hanna NN, Wayne JD, Hallahan DE, Hellman S, Weichselbaum RR (1996) Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 56(19):4311–4314

    PubMed  CAS  Google Scholar 

  • Meng Y, Efimova EV, Hamzeh KW, Darga TE, Mauceri HJ, Fu YX, Kron SJ, Weichselbaum RR (2012) Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine. Mol Ther 20(5):1046–1055

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Moore MW, Carbone FR, Bevan MJ (1988) Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell 54(6):777–785

    Article  PubMed  CAS  Google Scholar 

  • Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68(8):2561–2563

    Article  PubMed  CAS  Google Scholar 

  • Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of anti-tumor immunity. Cancer Res 61(13):5132–5136

    PubMed  CAS  Google Scholar 

  • Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22(2):238–244

    Article  PubMed  CAS  Google Scholar 

  • Peters HL, Yan Y, Solheim JC (2013) APLP2 regulates the expression of MHC class I molecules on irradiated Ewing’s sarcoma cells. Oncoimmunology 2(10):e26293

    Article  PubMed  PubMed Central  Google Scholar 

  • Pulendran B, Ahmed R (2006) Translating innate immunity into immunological memory: implications for vaccine development. Cell 124(4):849–863

    Article  PubMed  CAS  Google Scholar 

  • Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rachmawati NM, Fukudome K, Tsuneyoshi N, Bahrun U, Tsukamoto H, Yanagibashi T, Nagai Y, Takatsu K, Ohta S, Kimoto M (2013) Inhibition of antibody production in vivo by pre-stimulation of Toll-like receptor 4 before antigen priming is caused by defective B-cell priming and not impairment in antigen presentation. Int Immunol 25(2):117–128

    Article  PubMed  CAS  Google Scholar 

  • Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful anti-tumor immunotherapy. J Exp Med 203(5):1259–1271

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Takaku S, Terabe M, Ambrosino E, Peng J, Lonning S, McPherson JM, Berzofsky JA (2010) Blockade of TGF-beta enhances tumor vaccine efficacy mediated by CD8(+) T cells. Int J Cancer 126(7):1666–1674

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tokumasa N, Suto A, Kagami S, Furuta S, Hirose K, Watanabe N, Saito Y, Shimoda K, Iwamoto I, Nakajima H (2007) Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-gamma production and the induction of Th1 cell differentiation. Blood 110(2):553–560

    Article  PubMed  CAS  Google Scholar 

  • Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, Powell WS, Monneret G (2006) Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 177(9):6540–6547

    Article  PubMed  CAS  Google Scholar 

  • Wei YQ, Wang QR, Zhao X, Yang L, Tian L, Lu Y, Kang B, Lu CJ, Huang MJ, Lou YY, Xiao F, He QM, Shu JM, Xie XJ, Mao YQ, Lei S, Luo F, Zhou LQ, Liu CE, Zhou H, Jiang Y, Peng F, Yuan LP, Li Q, Wu Y, Liu JY (2000) Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine. Nat Med 6(10):1160–1166

    Article  PubMed  CAS  Google Scholar 

  • Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5(4):263–274

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grants 81123003 and 81301980) and China Postdoctoral Science Foundation (2013M542283).

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Guobo Shen.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Shen, G., Nie, W. et al. Irradiated tumor cells of lipopolysaccharide stimulation elicit an enhanced anti-tumor immunity. J Cancer Res Clin Oncol 140, 1815–1823 (2014). https://doi.org/10.1007/s00432-014-1721-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-014-1721-4

Keywords

Navigation