Neoadjuvant Salmonella typhimurium LVR01 restrains melanoma metastatic disease through a systemic response mediated by IFN-γ and CD8 + T cells

Attenuated Salmonella Typhimurium LVR01 has demonstrated potential in retarding primary melanoma growth; however, it rarely achieves complete remission as a monotherapy. While neoadjuvant LVR01 treatment before surgical resection significantly reduces metastatic frequency and promotes complete recovery in 50% of subjects, the mechanisms underlying this systemic protection remain poorly understood. B16F1 and B16F10 melanoma bearing mice were treated with intratumoral LVR01 and one week later primary tumor excision was performed. Systemic immunity was assessed through different tumor challenges (i.e. intravenous B16F10 lung colonization assay and unrelated Lewis Lung Carcinoma subcutaneous implantation), and adoptive splenocyte transfer. LVR01-mediated protection was tumor-specific and immune-mediated, as evidenced by the inability of treated-mice to control unrelated tumors and the increased anti-tumor capacity of transferred splenocytes. Notably, while LVR01 control of primary tumors is largely innate-driven, protection against metastatic dissemination was dependent on IFN-γ and CD8 + T cells. IFN-γ knockout and CD8-depleted mice exhibited significantly higher metastatic incidence and reduced survival. However, isolated splenic CD8 + T cells were insufficient to confer protection alone, suggesting a requirement for a broader immune network. These results reveal that Salmonella triggers a multifaceted immune response that evolves from an innate-driven primary defense to a systemic, tumor-specific adaptive response. This work elucidates the essential roles of IFN-γ and CD8 + T cells in preventing metastatic recurrence, supporting the clinical development of LVR01 as a potent neoadjuvant immunotherapy.