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

Mirjam E Hoekstra1, Laura Bornes2, Feline E Dijkgraaf1

  • 1Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

Nature Cancer
|June 23, 2020
PubMed

Insights

Activated CD8+ T cells secrete interferon-gamma (IFNγ), which spreads widely within tumors, influencing distant tumor cells. This immune response can increase PD-L1 and inhibit tumor growth, even in antigen-loss variants.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Signaling

Background:

  • Interferon-gamma (IFNγ) secreted by CD8+ T cells has known effects on tumor cells, including immune checkpoint induction and growth inhibition.
  • The spatial and temporal dynamics of IFNγ spread within the tumor microenvironment remain poorly understood.

Purpose of the Study:

  • To investigate the spatiotemporal spreading of IFNγ secreted by activated CD8+ T cells within a tumor.
  • To determine if long-range IFNγ signaling affects tumor cell behavior and growth.

Main Methods:

  • Multiday intravital imaging of tumors.
  • Analysis of IFNγ spread in tumors with spatially separated antigen-positive and -negative tumor cells.

Main Results:

  • IFNγ secreted by a small fraction of recognized tumor cells is sensed by a large portion of the tumor mass.
  • IFNγ response spreads over distances exceeding 800 µm.
  • Long-range IFNγ signaling induces PD-L1 expression and inhibits tumor growth.

Conclusions:

  • CD8+ T cell-secreted IFNγ modulates the behavior of remote tumor cells, including antigen-loss variants.
  • IFNγ plays a crucial role in coordinating anti-tumor immunity across the tumor landscape.
Keywords:
CD8+ T cellsIFNγ receptor signaling reporterIFNγ spreadingintravital imagingtumor immunology

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