Abstract
Immune activation within the tumor microenvironment is one promising approach to induce tumor regression. Certain viruses including oncolytic viruses such as the herpes simplex virus (HSV) and non-oncolytic viruses such as the lymphocytic choriomeningitis virus (LCMV) are potent tools to induce tumor-specific immune activation. However, not all tumor types respond to viro- and/or immunotherapy and mechanisms accounting for such differences remain to be defined. In our current investigation, we used the non-cytopathic LCMV in different human melanoma models and found that melanoma cell lines produced high levels of CCL5 in response to immunotherapy. In vivo, robust CCL5 production in LCMV infected Ma-Mel-86a tumor bearing mice led to recruitment of NK cells and fast tumor regression. Lack of NK cells or CCL5 abolished the anti-tumoral effects of immunotherapy. In conclusion, we identified CCL5 and NK cell-mediated cytotoxicity as new factors influencing melanoma regression during virotherapy.
Highlights
Melanoma accounts for the great majority of skin cancer related deaths
Comparing the three human melanoma cell lines in a murine xenograft model, Ma-Mel-86c Ma-Mel-86a and Ma-Mel-51 [36, 37], we found that lymphocytic choriomeningitis virus (LCMV) infection strongly suppressed growth of Ma-Mel-86a tumors (Figure 1A) and regressed tumor outgrowth in case of Ma-Mel-86c (Figure 1B)
Talimogene laherparepvec (T-VEC), is a herpes simplex based oncolytic virus that was recently approved for the treatment of advanced melanoma [43]
Summary
Melanoma accounts for the great majority of skin cancer related deaths. over the past few years, immunotherapy has dramatically changed the landscape of melanoma treatment. CD8+ T cells are considered to be the main anti-tumor effectors and their contribution to tumor regression has been shown to be of relevance in patients with melanoma and lung carcinoma [2, 3]. In contrast to CD8+ T cells, the role of NK cells in tumor regression has not been as thoroughly studied. There are some studies demonstrating that NK cells play critical roles in reducing lung metastases in mouse models [4,5,6]. NK cells are not frequently detected within tumor biopsies [7], and in melanoma, high levels of NK cell infiltrates generally correlate with strong tumor regression [7, 8]. Once NK cells are recruited into the tumor microenvironment, NK activating NKp46, NKp30, NKp44, NKG2D and inhibiting KIR, NKG2A receptors can recognize and be activated by tumor
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