Hoekstra and Bornes et al. created an IFNγ-sensing reporter (ISG) system and used intravital imaging to probe the space/time impact of IFNγ secreted from tumor-infiltrating T cells on ‘antigen (Ag)-loss’ tumor variants. Ag-specific CD8+ T cells were infused into immune deficient mice bearing tumors of intermingled Ag+GFP+ and Ag- ISG+ tumor cells. Even if Ag+ cells were only a small part of the tumor mass, IFNγ signaled IFNγR+Ag-ISG+ cells both near and, with time, distal (over 800 µm; 30-40 cell layers) from antigen encounter sites. IFNγ boosted PD-L1 on Ag-ISG+ IFNγR+ cells, enhanced their sensitivity to IFNγR-dependent deletion, and impaired tumor growth.
Contributed by Paula Hochman
ABSTRACT: T-cell-secreted interferon (IFN)-γ can exert pleiotropic effects on tumor cells that include induction of immune checkpoints and antigen presentation machinery components, and inhibition of cell growth. Despite its role as a key effector molecule, little is known about the spatiotemporal spreading of IFN-γ secreted by activated CD8+ T cells within the tumor environment. Using multiday intravital imaging, we demonstrate that T cell recognition of a minor fraction of tumor cells leads to sensing of IFN-γ by a large part of the tumor mass. Furthermore, imaging of tumors in which antigen-positive and antigen-negative tumor cells are separated in space reveals spreading of the IFN-γ response, reaching distances of >800 _m. Notably, long-range sensing of IFN-γ can modify tumor behavior, as shown by both induction of PD-L1 expression and inhibition of tumor growth. Collectively, these data reveal how, through IFN-γ, CD8+ T cells modulate the behavior of remote tumor cells, including antigen-loss variants.
Author Info: (1) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Molecular Pathology, Oncode Institu
Author Info: (1) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.(3) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
