Modulation of the host microenvironment by a common non-oncolytic mouse virus leads to inhibition of plasmacytoma development through NK cell activation

Abstract

Although many cells undergo transformation, few actually develop into tumours, due to successful mechanisms of immunosurveillance. To investigate whether an infectious agent may play a role in this process, the growth of a plasmacytoma was investigated in mice infected by lactate dehydrogenase-elevating virus. Acutely infected animals were significantly protected against tumour development. The mechanisms responsible for this protection were analysed in mice deficient for relevant immune cells or molecules and after in vivo cell depletion. This protection by viral infection correlated with NK cell activation and with IFN-c production. It might also be related to activation of NK/T-cells, although this remains to be proven formally. Therefore, our results indicated that infections with benign microorganisms may protect the host against cancer development, through non-specific stimulation of the host's innate immune system and especially of NK cells.

Lactate dehydrogenase-elevating virus enhances natural killer cell-mediated immunosurveillance of mouse mesothelioma development

“…Although other cytokines might also participate to this protective effect, we could observe involvement of IL-12, a classical NK cell activating cytokine, in LDV-induced protection, through modulation of IFN-γ secretion by these cells. This fits well with a previous report that anti-mesothelioma T lymphocyte response positively correlates with the production of this cytokine [35] and with the involvement of IFN-γ in LDV-mediated protection against plasmocytoma growth [13]. These observations confirm that IFN-γ is a major mediator of tumor immunosurveillance [3,13,36].…”

“…Our observation confirms also that NK cells play a major role in an efficient immunosurveillance against a range of tumors [1,13,14]. Distinct activation pathways are known to trigger different NK cell effector functions, including cytotoxicity and IFN-γ secretion.…”

“…Although T lymphocytes were clearly involved in the anti-mesothelioma response of normal animals, the role of NK cells could be observed in animals deprived of T lymphocytes, indicating that the mere activation of these NK cells was sufficient to provide at least some protection. This and other observations that experimental LDV infection reduces the development of other cancer types [11][12][13] through activation of the immune system rather than through direct oncolytic effect may thus support the hypothesis that modulation of the immune microenvironment by some pathogens leads to enhancement of immunosurveillance capacity of the infected host against some cancer types.…”

“…4b, addition of 0.9 U/ml IFN-γ to AB1 cell cultures strongly reduced their proliferation. In contrast the same treatment had no effect on P815 cells, a mastocytoma cell line on which LDV infection has been reported to have no protective effect [13]. This sensitivity of AB1 cells to IFNγ was found in two independent experiments.…”

“…In contrast, viruses that lytically infect cancer cells induce tumor regression. Moreover, alteration of immune microenvironment by viruses may also lead either to enhancement or suppression of cancer development [11][12][13][14].…”