The Spread of Interferon-γ in Melanomas is Highly Spatially Confined, Driving Non-Genetic Variability in Tumor Cells

Abstract

Interferon-{gamma} (IFN{gamma}) is a critical anti-tumor cytokine that has varied effects on different cell types. The global effect of IFN{gamma} in the tumor depends on which cells it acts upon and the spatial extent of its spread. Reported measurements of IFN{gamma} spread vary dramatically in different contexts, ranging from nearest-neighbor signaling to perfusion throughout the entire tumor. Here, we apply theoretical considerations to experiments both in vitro and in vivo to study the spread of IFN{gamma} in melanomas. We observe spatially confined niches of IFN{gamma} signaling in 3-D mouse melanoma cultures and human tumors that generate cellular heterogeneity in gene expression and alter the susceptibility of affected cells to T cell killing. Widespread IFN{gamma} signaling only occurs when niches overlap due to high local densities of IFN{gamma}-producing T cells. We measured length scales of [~]30-40m for IFN{gamma} spread in B16 mouse melanoma cultures and human primary cutaneous melanoma. Our results are consistent with IFN{gamma} spread being governed by a simple diffusion-consumption model, and offer insight into how the spatial organization of T cells contributes to intra-tumor heterogeneity in inflammatory signaling, gene expression, and immune-mediated clearance. Solid tumors are often viewed as collections of diverse cellular "neighborhoods": our work provides a general explanation for such non-genetic cellular variability due to confinement in the spread of immune mediators.