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Tumor Suppression by Anti-Fibroblast Activation Protein Near-Infrared Photoimmunotherapy Targeting Cancer-Associated
Raisa A Glabman1,2, Colleen P Olkowski1, Hannah A Minor1
1Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Cancer-associated fibroblasts (CAFs) constitute a prominent cellular component of the tumor stroma, with various pro-tumorigenic roles. Numerous attempts to target fibroblast activation protein (FAP), a highly expressed marker in immunosuppressive CAFs, have failed to demonstrate anti-tumor efficacy in human clinical trials. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor therapy that utilizes an antibody-photo-absorbing conjugate activated by near-infrared light. In this study, we examined the therapeutic efficacy of CAF depletion by NIR-PIT in two mouse tumor models. Using CAF-rich syngeneic lung and spontaneous mammary tumors, NIR-PIT against FAP or podoplanin was performed. Anti-FAP NIR-PIT effectively depleted FAP+ CAFs, as well as FAP+ myeloid cells, and suppressed tumor growth, whereas anti-podoplanin NIR-PIT was ineffective. Interferon-gamma production by CD8 T and natural killer cells was induced within hours after anti-FAP NIR-PIT. Additionally, lung metastases were reduced in the treated spontaneous mammary cancer model. Depletion of FAP+ stromal as well as FAP+ myeloid cells effectively suppressed tumor growth in bone marrow chimeras, suggesting that the depletion of both cell types in one treatment is an effective therapeutic approach. These findings highlight a promising therapy for selectively eliminating immunosuppressive FAP+ cells within the tumor microenvironment.
Insights
Near-infrared photoimmunotherapy targeting fibroblast activation protein (FAP) effectively depletes immunosuppressive cancer-associated fibroblasts and myeloid cells, suppressing tumor growth and reducing metastases in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Cancer-associated fibroblasts (CAFs) promote tumor growth and immune suppression.
- Targeting fibroblast activation protein (FAP) on CAFs has shown limited success in clinical trials.
- Near-infrared photoimmunotherapy (NIR-PIT) offers a selective tumor-targeting approach.
Purpose of the Study:
- To evaluate the therapeutic efficacy of NIR-PIT targeting FAP for CAF depletion in preclinical cancer models.
- To assess the impact of FAP-targeted NIR-PIT on tumor growth, immune cell activation, and metastasis.
Main Methods:
- NIR-PIT targeting FAP and podoplanin was performed in syngeneic lung and spontaneous mammary tumor mouse models.
- Tumor growth, FAP+ cell depletion, and immune cell responses (IFN-gamma) were analyzed.
- Bone marrow chimeras were used to investigate the role of FAP+ stromal and myeloid cells.
Main Results:
- Anti-FAP NIR-PIT effectively depleted FAP+ CAFs and FAP+ myeloid cells, suppressing tumor growth.
- Anti-podoplanin NIR-PIT showed no significant anti-tumor effect.
- Anti-FAP NIR-PIT induced interferon-gamma production by CD8 T and NK cells.
- Lung metastases were reduced in the spontaneous mammary cancer model.
Conclusions:
- Targeting FAP+ cells, including both stromal and myeloid populations, via NIR-PIT is a promising therapeutic strategy.
- This approach effectively suppresses tumor growth and may reduce metastasis.
- NIR-PIT offers a selective method for eliminating immunosuppressive cells within the tumor microenvironment.
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