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. Articles Nature CaNCerExtended Data Fig. 5 | analysis of T cell mediated loss of ag-presenting tumor cells over time. a, relative GFP + volume in tumors from imaging experiments described in Fig. 2 quantified over time. Mean and SEM are depicted for n=5 mice (n=5 mice for time 0, 16, 24, and 32 h; n=4 for 40, 48, and 72 h; n=3 for 120 h, from data obtained in all independent experiments. b, The distance between CFP + bystander tumor cells and the closest GFP + Ag + tumor cell was determined at indicated time points from tumors described in Fig. 2 for n=2 mice. Data are obtained from two independent experiments, boxplot presenting the minimum, 25 th percentile, median, 75 th percentile and the maximum For total sample size per timepoint see Source Data ED_Fig5_source table.

CD137-stimulated cytotoxic T lymphocytes exert superior tumour control due to an enhanced antimitotic effect on tumour cells

“…In our data CTL apoptosis increased over time, so we introduced a resistance variable R to account for this. This is consistent with recent reports that long range IFN-γ signalling can cause upregulation of PD-L1 in cells across distances of up to 800 [26] ; or that IFN-γ-dependent invasion of m μ myeloid-derived suppressor cells could be the major source of suppression [27] ; or other immune checkpoint death receptors such as FAS-L [28] ; or perhaps competition between tumour cells and CTLs for nutrients was a primary mediator of CTL apoptosis in our model, since both activated CTLs and tumour cells rely heavily on anaerobic glycolysis or glycolysis as sources of fuel [29] , and interactions between CTLs and stromal cells resulted in catastrophic destruction of tumour vasculature [30] , which ought to result in a reduction in glucose supply to the tumour and might account for increased apoptosis of CTLs over time. It would be useful to acquire more experimental data which could shed light on the reasons for this apparent time-increasing apoptosis rate.…”

“…Invading CTLs have 2 different T effects on tumour cells: either killing which occurs at rate (CTL -1 day -1 ), or induction of k e the quiescent state which happens at rate (CTL -1 day -1 ). Our quiescent state is k q motivated by observations of an -dependent cell-cycle arrest in B16F10 melanoma F N γ I after ACT [20] , which we previously implicated in control of murine EL4 lymphoma [6] and for which there is also evidence in ovarian and breast carcinoma models [26] . In B16F10 melanoma, quiescent tumour cells recover from CTL induced cell cycle arrest after a few days [20] .…”

Roles of IFN-γ in tumor progression and regression: a review

“…IFNGR-interferon gamma receptor; IDILs-interferon-driven inhibitory ligands; TILs-tumor infiltrating lymphocytes; ISGs-interferon signature genes; ICB-immune checkpoint blockade; TME-tumor microenvironment Thibaut et al recently suggested a model in which tumor-reactive T-cells secrete IFN-γ, which diffuses extensively to alter the TME in distant areas. The prolonged activity of IFN-γ has been shown to be crucial for antitumor immune response [107] as shown by induction of PD-L1 expression and inhibition of tumor growth [108]. Furthermore, Zhang et al proposed that IFN-γ may be a good therapeutic option for improving the efficacy of PD-1 blockade therapy for pancreatic cancer by preventing the trafficking of CXCR2+ CD68+ immunosuppressive macrophages to the TME by blocking the CXCL8-CXCR2 axis [109].…”

Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions

“…Interactions with several targets may provide signal integration and facilitate amplification of the immune response or target cell elimination. Furthermore, polarized secretion could still induce signal spreading as the immunological synapse does not spatially restrict IFNγ secretion by CTLs, allowing IFNγ bystander activity important to alter tumor environment (Sanderson et al, 2012;Hoekstra et al, 2020;Thibaut et al, 2020).…”