Macrophage Transcriptomic Alterations Driven by Alphavirus-Based Cancer Immunotherapy Vectors

Area of Science:

• Immunology
• Virology
• Cancer Biology

Background:

• Tumor-associated macrophages (TAMs) often adopt a pro-tumorigenic M2 phenotype, hindering cancer therapy.
• Reprogramming TAMs to an anti-tumor M1 phenotype using viral immunotherapy vectors is a promising strategy.
• Understanding the mechanisms of macrophage reprogramming by viral vectors is crucial for effective cancer treatment.

Purpose of the Study:

• To investigate the transcriptomic alterations in macrophages induced by Semliki Forest virus (SFV) vectors.
• To determine how SFV-mediated gene delivery to cancer cells influences macrophage polarization.
• To explore the potential of alphavirus vectors for reprogramming macrophages towards an anti-cancer phenotype.

Main Methods:

• Murine mammary cancer cells were infected with SFV vectors carrying TNFα or IFNγ genes.
• Conditioned media from infected cancer cells were used to treat bone marrow-derived macrophages (BMDMs).
• Transcriptomic analysis (RNA sequencing) was performed on treated BMDMs to assess gene expression changes.

Main Results:

• SFV-infected cancer cells modulated cytokine profiles, reducing immunosuppression and increasing inflammation.
• Macrophage treatment with SFV-conditioned media upregulated genes related to antigen presentation, interferon response, and M1 polarization.
• SFV/IFNγ inhibited pro-tumorigenic pathways (angiogenesis, glycolysis, ECM remodeling) and increased cytotoxic T-lymphocyte attractants.
• SFV vectors upregulated PD-L1 (Cd274) expression on macrophages.

Conclusions:

• Alphavirus-mediated gene delivery to cancer cells can induce pro-inflammatory responses in macrophages, reprogramming them to an anti-cancer M1 phenotype.
• SFV vectors show potential for modulating the tumor microenvironment and enhancing anti-tumor immunity.
• Combining SFV/IFNγ with immune checkpoint inhibitors may improve therapeutic outcomes by counteracting virus-induced suppressive signals.