The spread of interferon-γ in melanomas is highly spatially confined, driving nongenetic variability in tumor cells

Edoardo Centofanti, Chad Wang, Sandhya Iyer, Oleg Krichevsky, Alon Oyler-Yaniv, Jennifer Oyler-Yaniv

Research output: Contribution to journalArticlepeer-review

Abstract

Interferon-γ (IFNγ) is a critical antitumor cytokine that has varied effects on different cell types. The global effect of IFNγ in the tumor depends on which cells it acts upon and the spatial extent of its spread. Reported measurements of IFNγ 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 IFNγ in melanomas. We observe spatially confined niches of IFNγ 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 IFNγ signaling only occurs when niches overlap due to high local densities of IFNγ-producing T cells. We measured length scales of ∼30 to 40 μm for IFNγ spread in B16 mouse melanoma cultures and human primary cutaneous melanoma. Our results are consistent with IFNγ spread being governed by a simple diffusion-consumption model and offer insight into how the spatial organization of T cells contributes to intratumor 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 nongenetic cellular variability due to confinement in the spread of immune mediators.

Original languageEnglish
Article numbere2304190120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number35
DOIs
StatePublished - 1 Jan 2023

Keywords

  • cytokine signaling
  • interferon-γ
  • melanoma
  • quantitative biology
  • tumor-infiltrating lymphocytes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'The spread of interferon-γ in melanomas is highly spatially confined, driving nongenetic variability in tumor cells'. Together they form a unique fingerprint.

Cite this