Poly (I:C) enhances the anti-tumor activity of canine parvovirus NS1 protein by inducing a potent anti-tumor immune response
- 338 Downloads
The canine parvovirus NS1 (CPV2.NS1) protein selectively induces apoptosis in the malignant cells. However, for an effective in vivo tumor treatment strategy, an oncolytic agent also needs to induce a potent anti-tumor immune response. In the present study, we used poly (I:C), a TLR3 ligand, as an adjuvant along with CPV2.NS1 to find out if the combination can enhance the oncolytic activity by inducing a potent anti-tumor immune response. The 4T1 mammary carcinoma cells were used to induce mammary tumor in Balb/c mice. The results suggested that poly (I:C), when given along with CPV2.NS1, not only significantly reduced the tumor growth but also augmented the immune response against tumor antigen(s) as indicated by the increase in blood CD4+ and CD8+ counts and infiltration of immune cells in the tumor tissue. Further, blood serum analysis of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were significantly upregulated in the treatment group indicating activation of cell-mediated immune response. The present study reports the efficacy of CPV2.NS1 along with poly (I:C) not only in inhibiting the mammary tumor growth but also in generating an active anti-tumor immune response without any visible toxicity. The results of our study may help in developing CPV2.NS1 and poly (I: C) combination as a cancer therapeutic regime to treat various malignancies.
KeywordsApoptosis NS1 Poly (I:C) TLR3 Breast cancer Cancer vaccine adjuvant Anti-tumor immune response
The authors are thankful to the Director, Indian Veterinary Research Institute, Izatnagar-243 122, UP, India, for providing necessary facilities and National Agricultural Innovative Project (reference C4/C3001) for providing funding to carry out the work. We are also thankful to Dr. Rajendra Singh, Head, Division of Veterinary Pathology and to Dr. K.P. Singh for providing facilities to perform histopathology and immunohistochemistry.
Compliance with ethical standards
The experiments were carried out as per the guidelines and approval of the Institute Animal Ethics Committee and Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA).
Conflicts of interest
- 14.Santra L, Rajmani RS, Ravi Kumar GVPPS, Saxena S, Dhara SK, Kumar A, Sahoo AP, Singh LV, Desai GS, Chaturvedi U, Kumar S, Tiwari AK. Non-structural protein 1 (NS1) gene of canine parvovirus-2 regresses chemically induced skin tumors in Wistar rats. Res Vet Sci. 2014. doi: 10.1016/j.rvsc.2014.07.024.PubMedGoogle Scholar
- 34.Yu CCW, Fletcher CD, Newman PL, Goodlad JR, Burton JC, Levison DA. A comparison of proliferating cell nuclear antigen (PCNA) immunostaining, nucleolar organizer region (AgNOR) staining, and histological grading in gastrointestinal stromal tumours. J Pathol. 1992;166(2):147–52.CrossRefPubMedGoogle Scholar
- 36.Doley J, Singh LV, Kumar GR, Sahoo AP, Saxena L, Chaturvedi U, Saxena S, Kumar R, Singh PK, Rajmani RS, Santra L, Palia SK, Tiwari S, Harish DR, Kumar A, Desai GS, Gupta S, Gupta SK, Tiwari AK. Canine parvovirus type 2a (CPV-2a)-induced apoptosis in MDCK involves both extrinsic and intrinsic pathways. Appl Biochem Biotechnol. 2014;172(1):497–508.CrossRefPubMedGoogle Scholar
- 45.Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, et al. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med. 2003;198:1741–52.CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Bhoopathi P, Quinn BA, Gui Q, Shen XN, Grossman SR, Das SK, et al. Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine–polycytidylic acid. Cancer Res. 2014.Google Scholar
- 60.Folkman J (2003) Angiogenesis and apoptosis. In: Seminars in cancer biology. 13(2):159–67. Academic Press.Google Scholar
- 67.Moehler MH, Zeidler M, Wilsberg V, Cornelis JJ, Woelfel T, Rommelaere J, Galle PR, Heike M. Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells. Hum Gene Ther. 2005;16(8):996–1005.CrossRefPubMedGoogle Scholar
- 69.Nüesch JP, Rommelaere J. Tumor suppressing properties of rodent parvovirus NS1 proteins and their derivatives. Anticancer genes. London: Springer; 2014. p. 99–124.Google Scholar
- 76.Paone A, Galli R, Gabellini C, Lukashev D, Starace D, Gorlach A, De Cesaris P, Ziparo E, Del Bufalo D, Sitkovsky MV, Filippini A. Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1α. Neoplasia. 2010;12(7):539–49.CrossRefPubMedPubMedCentralGoogle Scholar