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A Macrophage-Tumor Spheroid Co-Invasion Assay
Published on: January 24, 2025
In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation
Marco Notaro1,2, Maristella Borghetti1,2, Chiara Bresesti1
1Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Abstract:
Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.
Insights
Arming liver macrophages in vivo with tumor antigens, IFNα, and IL-12 triggers potent anti-tumor immunity, leading to liver metastasis regression. This approach expands and rejuvenates tumor-reactive T cells for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Cellular Biology
Background:
- Liver metastases remain a significant challenge in cancer therapy.
- Current treatments for liver metastases have limitations.
Purpose of the Study:
- To investigate the potential of in vivo armed macrophages for treating liver metastases.
- To elucidate the mechanisms by which armed macrophages induce anti-tumor responses.
Main Methods:
- Macrophages were engineered in vivo to co-express tumor antigens, IFNα, and IL-12.
- Tumor-reactive CD8+ T cell expansion and function were analyzed.
- Antigen-presenting cell reprogramming and cellular interactions were studied.
- Efficacy was tested in mouse models of colorectal cancer and melanoma liver metastases.
Main Results:
- In vivo armed macrophages induced robust anti-tumor immune responses and liver metastasis regression.
- Tumor-reactive CD8+ T cells were expanded and acquired features of progenitor exhausted T cells.
- IFNα and IL-12 reprogrammed antigen-presenting cells and rescued T cell functions.
- The approach showed efficacy across different liver metastasis models.
Conclusions:
- In vivo armed liver macrophages offer a promising strategy for treating liver metastases.
- This immunotherapy expands and rejuvenates tumor-reactive T cells.
- The findings support the translational potential of this approach for liver cancer treatment.
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