Abstract

Immune activation within the tumor is one promising approach to induce immune-mediated tumor regression. Viruses are promising approaches to induce tumor-specific immune activation, however not all tumor types respond to virotherapy and mechanisms explaining such differences remains to be defined. Here, by using the lymphocytic choriomeningitis virus (LCMV) in different tumor cell lines, we found that some human melanoma cell lines responded strongly with CCL5 production especially mamel-86A responded very well to the arenavirus therapy, when the mamel-86A tumor bearing NodScid mice were treated with the LCMV there was the complete tumor regression and mice were tumor free at one point, but some tumors like mamel-51 showed massive resistance to the arenavirus therapy, To further address this question of robust tumor regression in case of mamel-86A and strong resistance towards LCMV therapy by mamel-51. We performed both in-vivo and in-vitro experiments and we discovered that the tumors that responded well to the LCMV therapy showed enhanced CCL5 production upon LCMV infection while as in case of non-responding tumors there was indigent CCL5 production, this variation in the chemokine profile upon the viral therapy further gave us the clue that there must be different immune cells infiltrate in the tumor microenvironment both in responding and non-responding tumor models and upon further investigation we discovered that there is massive NK cell infiltrate to the tumor site upon LCMV infection but this scenario only happens in case of responding tumor (Mamel-86A) while as in case of non-responding tumor there was very poor NK cell infiltrate, so higher CCL5 drives more NK cells to the site of the tumor and vice versa. The next interesting finding in our study was that the production of CCL5 in the Mamel-86A tumor cells is dependent on PI3K pathway; blockade of PI3K by using the inhibitors abrogates the production of CCL5. To further, address this massive antitumor effects we used NK cell deficient mice, these mice showed faster tumor growth and poor antitumor effects even after LCMV therapy but since the antitumor effects in our experimental model is also linked to the CCL5, this further prompted us to look how the tumors will be behave upon the blockage of CCR5, upon in-vivo experimental settings we found out that blockade of CCL5 leads to the enhanced growth of tumor Thus we can say depletion of NK cells or CCL5 abolished anti-tumoral effects of virotherapy. In conclusion, we identified CCL5 and NK cell mediated cytotoxicity as a new mechanism leading to regression of melanoma and explaining differences in the immunological response to virotherapy.

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