Role of the CXCR3 Chemokine Receptor Axis in the Combination of Oncolytic Vesicular Stomatitis Virus Therapy and Natural Killer T Cell Immunotherapy in Melanoma

Abstract

Advanced melanoma is highly metastatic and resistant to chemotherapies, with a 5-year survival rate below 30%. This study investigated Natural Killer T (NKT) cell-based immunotherapy in combination with oncolytic vesicular stomatitis virus (VSV-ΔM51). VSV-ΔM51 infection increases production of CXCR3 ligands CXCL9, -10, and -11, potentially recruiting CXCR3-expressing NKT cells into the tumor microenvironment; however, the specific role of the CXCR3 axis in treatment efficacy is unknown. Responses to VSV-ΔM51 and NKT cell immunotherapy were tested using a melanoma model. Combined treatments enhanced survival duration compared to monotherapies in both wild-type and CXCR3-/- mice. Loss of CXCR3 impaired accumulation of NKT cells within tumors, but did not impair other immune populations. CXCR3-/- mice exhibited improved responses to VSV-ΔM51, with increased viral persistence post-treatment. These results demonstrate that combined VSV-ΔM51 and NKT cell immunotherapy provides superior survival benefits compared to monotherapies. However, the CXCR3 axis appears ultimately dispensable for combined therapy.