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Targeted Photo-Induced Elimination of Tumor-Associated Macrophages Suppresses Cancer Progression in a Murine Model
Kohei Nakajima1, Tomomi Uchiyama1, Kazuki Funayama1
1Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.
Abstract:
Tumor-associated macrophages (TAMs) are key components of the immunosuppressive tumor microenvironment (TME) and represent attractive therapeutic targets to enhance antitumor immunity. However, systemic TAM-depletion strategies targeting colony-stimulating factor 1 receptor (CSF1R) are associated with the risk of off-target toxicity due to the depletion of macrophages in healthy tissues. Here, we investigated the potential of near-infrared photoimmunotherapy (NIR-PIT) as a strategy for selective, photo-induced elimination of TAMs. The Fab fragment of an anti-CSF1R antibody was conjugated with the photosensitizer IRDye 700DX (IR700), and the therapeutic effects of the conjugate were evaluated in a murine cancer model. Upon NIR light irradiation, Fab-IR700 significantly suppressed tumor growth and improved overall survival of the tumor-bearing mice. Notably, repeated NIR-PIT cycles enhanced therapeutic outcomes and induced durable anticancer effects, as indicated by the rejection of reimplanted cancer cells. Flow cytometry and histological analyses confirmed TAM depletion and significant alterations in the intra-tumoral immune cell populations posttreatment. Overall, CSF1R-targeted NIR-PIT can effectively eliminate TAMs without systemic toxicity, thus presenting a promising strategy to remodel the TME toward an antitumor state and synergize with other immunotherapies against refractory tumors.
Insights
Near-infrared photoimmunotherapy targeting colony-stimulating factor 1 receptor (CSF1R) selectively eliminates tumor-associated macrophages (TAMs). This approach suppresses tumor growth and enhances antitumor immunity without systemic toxicity, offering a promising cancer therapy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Tumor-associated macrophages (TAMs) create an immunosuppressive tumor microenvironment (TME).
- Targeting colony-stimulating factor 1 receptor (CSF1R) on TAMs is a therapeutic strategy, but systemic depletion risks off-target toxicity.
- Developing selective TAM elimination methods is crucial for effective cancer immunotherapy.
Purpose of the Study:
- To investigate near-infrared photoimmunotherapy (NIR-PIT) for selective TAM elimination.
- To evaluate the therapeutic efficacy of CSF1R-targeted NIR-PIT in a murine cancer model.
- To assess the potential of NIR-PIT to remodel the TME and enhance antitumor immunity.
Main Methods:
- Conjugating an anti-CSF1R antibody fragment (Fab) with a photosensitizer (IRDye 700DX).
- Administering the conjugate and irradiating with near-infrared (NIR) light in tumor-bearing mice.
- Analyzing tumor growth, survival, immune cell populations, and histology post-treatment.
Main Results:
- NIR-PIT with Fab-IR700 significantly suppressed tumor growth and improved survival.
- Repeated NIR-PIT cycles led to durable anticancer effects, including rejection of reimplanted tumors.
- Treatment effectively depleted TAMs and altered intra-tumoral immune cell composition without systemic toxicity.
Conclusions:
- CSF1R-targeted NIR-PIT offers a selective method for eliminating TAMs.
- This approach can remodel the TME towards an antitumor state.
- NIR-PIT is a promising strategy to enhance immunotherapy for refractory tumors.
