Pro-Inflammatory Macrophage Phenotype Skewing Induced by Tumor Treating Fields (TTFields)

Area of Science:

• Immunology
• Oncology
• Biophysics

Background:

• Tumor-associated macrophages (TAMs) often exhibit an immunosuppressive M2 phenotype, promoting tumor growth.
• Reprogramming TAMs to a pro-inflammatory M1 state is a promising cancer therapy strategy.
• Tumor Treating Fields (TTFields) are an FDA-approved electric-field therapy with known anti-mitotic effects.

Purpose of the Study:

• To investigate the direct impact of TTFields on macrophage activation and function.
• To determine if TTFields can reprogram immunosuppressive TAMs towards an anti-tumorigenic phenotype.

Main Methods:

• Murine bone marrow-derived macrophages (BMDMs) were polarized to M1 or M2 phenotypes and exposed to TTFields.
• Macrophage signaling pathways, including GEF-H1, NF-κB, and AP-1, were analyzed.
• In vivo studies utilized an orthotopic murine lung cancer model to assess TTFields' effects on tumor burden and TAM phenotype.

Main Results:

• TTFields activated GEF-H1, NF-κB, and AP-1 signaling pathways in macrophages.
• TTFields reprogrammed M2 macrophages by increasing MHC-II and CD80, decreasing Arg1, and elevating pro-inflammatory cytokines (CXCL1, IL-6, IL-1β, IL-12p70).
• In vivo, TTFields reduced tumor burden and increased iNOS expression in TAMs, indicating a shift towards a pro-inflammatory state.

Conclusions:

• TTFields directly reprogram macrophages, shifting them from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype.
• This direct immunomodulatory effect of TTFields suggests a novel mechanism for enhancing anti-tumor immunity.
• TTFields represent a potential therapeutic strategy to re-educate the tumor microenvironment for improved cancer treatment outcomes.