TAMs-mediated resistance to oncolytic virus M1 in solid tumors

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• Oncolytic virus M1 (OVM) shows antitumor potential via immunogenic cell death and CD8+ T-cell activation.
• In vivo efficacy of OVM is variable, with resistance mechanisms poorly understood.
• Tumor-associated macrophages (TAMs) are immunosuppressive and may limit OVM therapy.

Purpose of the Study:

• To investigate the role of TAMs in OVM resistance.
• To determine if TAM depletion enhances OVM antitumor activity.
• To elucidate the mechanisms underlying TAM-mediated OVM resistance.

Main Methods:

• Utilized syngeneic mouse models of colorectal, pancreatic, prostate, and melanoma cancers.
• Depleted TAMs using clodronate liposomes or CSF1R antibodies.
• Assessed viral load, immune cell infiltration (flow/mass cytometry), and gene expression (RT-qPCR, RNA-seq).

Main Results:

• TAM infiltration correlated positively with OVM resistance.
• TAM depletion increased intratumoral viral load and CD8+ T-cell responses (GZMB+).
• RNA-seq revealed enhanced antiviral and T-cell pathways upon TAM depletion; CD8+ T-cell depletion abrogated therapeutic benefits.

Conclusions:

• TAMs, especially M1-like subsets, mediate OVM resistance by limiting viral persistence and suppressing CD8+ T-cell immunity.
• Targeting TAMs significantly improves OVM antitumor efficacy in solid tumors.
• Combination strategies involving TAM-targeting agents are promising for enhancing oncolytic virotherapy.