Long-distance modulation of bystander tumor cells by CD8+ T-cell-secreted IFN-γ

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 µm. 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.