Tumor Suppression by Anti-Fibroblast Activation Protein Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts.

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.

SUBMITTER: Glabman RA 

PROVIDER: S-EPMC10813865 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature