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Review
. 2021 Apr:69:65-71.
doi: 10.1016/j.coi.2021.03.016. Epub 2021 Apr 13.

Modulation of the tumor micro-environment by CD8+ T cell-derived cytokines

Mirjam E Hoekstra  1 , Saskia V Vijver  1 , Ton N Schumacher  2
Affiliations
Review

Modulation of the tumor micro-environment by CD8+ T cell-derived cytokines

Mirjam E Hoekstra et al. Curr Opin Immunol. 2021 Apr.

Abstract

Upon their activation, CD8+ T cells in the tumor micro-environment (TME) secrete cytokines such as IFNγ, TNFα, and IL-2. While over the past years a major interest has developed in the antigenic signals that induce such cytokine release, our understanding of the cells that subsequently sense these CD8+ T-cell secreted cytokines is modest. Here, we review the current insights into the spreading behavior of CD8+ T-cell-secreted cytokines in the TME. We argue for a model in which variation in the mode of cytokine secretion, cytokine half-life, receptor-mediated clearance, cytokine binding to extracellular components, and feedback or forward loops, between different cytokines or between individual tumors, sculpts the local tissue response to natural and therapy-induced T-cell activation in human cancer.

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Conflict of interest statement

Declarations of interest: none

Figures

Figure 1
Figure 1. Potential factors affecting cytokine spreading in the TME.
The spatiotemporal behavior of CD8+ T cell cytokines is likely to depend on A) the mode of cytokine secretion by the producing cell, and B) environmental factors influencing receptor-mediated clearance, cytokine half-life, cytokine binding to extracellular components, and feedback/ feedforward loops. Variation between these factors is expected between tumors, due to e.g. their genetic make-up, immune infiltrate, molecular ECM structure, level of hypoxia, and nutrient availability.
See this image and copyright information in PMC

References

Recommended reading

    1. Hoekstra ME, et al. Long-distance modulation of bystander tumor cells by CD8(+) T cell-secreted IFNgamma. Nat Cancer. 2020;1(3):291–301. [• Using a GAS based IFNγ sensing reporter and multiday intravital imaging of tumors in mice, this paper reveals sensing of CD8+ T-cell secreted IFNγ over large distances in tumor masses. The observed long-range sensing of IFNγ is also shown to modify the behavior of antigen-negative tumor cells, as demonstrated by both induction of PD-L1 expression and inhibition of tumor growth.] - PMC - PubMed
    1. Thibaut R, et al. Bystander IFN-gamma activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment. Nat Cancer. 2020;1(3):302–314. [• Using intravital imaging and a reporter for STAT1 translocation, this paper demonstrates that CD8+ T-cell derived IFNγ diffuses extensively in mouse tumors to alter the tumor microenvironment in distant areas. Additionally, single-cell RNA-sequencing data from melanoma patients provide evidence that IFNγR signaling also may occur in bystander cells in human tumors.] - PMC - PubMed
    1. Oyler-Yaniv J, et al. Catch and Release of Cytokines Mediated by Tumor Phosphatidylserine Converts Transient Exposure into Long-Lived Inflammation. Mol Cell. 2017;66(5):635–647.:e7. [•• Combining mathematical modeling with various experimental approaches including a mouse model of thyroid cancer, this paper demonstrates that IFNγ is captured by phosphatidylserine on the surface of viable tumor cells in vivo, followed by its slow release to drive prolonged transcription of IFNγ responsive genes.] - PMC - PubMed
    1. Gordon-Alonso M, et al. Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun. 2017;8(1):793. [•• This paper reveals that the extracellular matrix protein galectin-3 binds IFNγ and reduces its diffusion through the tumor matrix in vivo.] - PMC - PubMed
    1. Oyler-Yaniv A, et al. A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System. Immunity. 2017;46(4):609–620. [•• Using the combination of mathematical modeling and in vitro and in vivo assays, this study demonstrates that the spatial reach of CD4+ T-cell derived IL-2 in lymph nodes is primarily governed by the local density of IL-2 consuming cells. These data suggest that IL-2 penetration in tissues is primarily regulated by a diffusion-consumption mechanism.] - PMC - PubMed

References

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