武装溶瘤黏液瘤病毒在免疫健全小鼠中诱导针对实体瘤的全身性抗肿瘤免疫

Oncolytic viruses expressing immunostimulatory transgenes can enhance immune cells recruitment into the tumor bed and activate potent antitumor immune responses. In this study, we evaluated oncolytic activity of recombinant myxoma virus (MYXV) variants expressing murine LIGHT, murine mIL-15, or IL-15Rα-IL-15 fusion protein.

All recombinant MYXVs demonstrated similar replication kinetics and cytotoxic activity in cancer cell lines. Their therapeutic efficacy was further assessed in a bilateral tumor model in immunocompetent mice, where only one tumor received intratumoral treatment.

We observed significant tumor regression in both injected and uninjected contralateral tumors following treatment with MYXV expressing IL-15Rα-IL-15 (vMyx-IL15Rα) or mLIGHT (vMyx-mLIGHT), indicating the activation of systemic antitumor immunity.

Additionally, vMyx-IL15Rα- treated mice survived significantly longer than any of the other treatments. Analysis of tumor-infiltrating lymphocytes revealed that vMyx-IL15Rα increased effector memory CD8 + T cells, natural killer (NK) cells, and NK-T cells, whereas vMyx-mLIGHT enhanced infiltration of effector memory CD4 + T cells and dendritic cells.

Furthermore, serum cytokine profiling showed increased levels of type I antitumor cytokines and reduced levels of protumor inflammatory cytokines and chemokines.

These findings demonstrate that arming MYXV with immunostimulatory cytokines enhances both local and systemic antitumor activity by remodeling the tumor microenvironment and promoting effective immune responses.