Bystander IFN-γ activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
entrez:
18
8
2020
pubmed:
18
8
2020
medline:
18
8
2020
Statut:
ppublish
Résumé
The cytokine IFN-γ produced by tumor-reactive T cells is a key effector molecule with pleiotropic effects during anti-tumor immune responses. While IFN-γ production is targeted at the immunological synapse, its spatiotemporal activity within the tumor remains elusive. Here, we report that while IFN-γ secretion requires local antigen recognition, IFN-γ diffuses extensively to alter the tumor microenvironment in distant areas. Using intravital imaging and a reporter for STAT1 translocation, we provide evidence that T cells mediate sustained IFN-γ signaling in remote tumor cells. Furthermore, tumor phenotypic alterations required several hours of exposure to IFN-γ, a feature that disfavored local IFN-γ activity over diffusion and bystander activity. Finally, single-cell RNA-seq data from melanoma patients also suggested bystander IFN-γ activity in human tumors. Thus, tumor-reactive T cells act collectively to create large cytokine fields that profoundly modify the tumor microenvironment.
Identifiants
pubmed: 32803171
doi: 10.1038/s43018-020-0038-2
pmc: PMC7115926
mid: EMS88525
pii: 10.1038/s43018-020-0038-2
doi:
Substances chimiques
Cytokines
0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
302-314Subventions
Organisme : European Research Council
ID : 741167
Pays : International
Commentaires et corrections
Type : CommentIn
Déclaration de conflit d'intérêts
Competing interests statement The authors declare no competing interests.
Références
Kaplan, D. H. et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl Acad. Sci. USA 95, 7556–7561 (1998).
pubmed: 9636188
doi: 10.1073/pnas.95.13.7556
pmcid: 22681
Street, S. E., Cretney, E. & Smyth, M. J. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97, 192–197 (2001).
pubmed: 11133760
doi: 10.1182/blood.V97.1.192
Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).
pubmed: 17063185
doi: 10.1038/nri1961
Garris, C. S. et al. Successful anti-PD-1 cancer immunotherapy requires T cell–dendritic cell crosstalk involving the cytokines IFN-gamma and IL-12. Immunity 49, 1148–1161 e1147 (2018).
pubmed: 30552023
pmcid: 6301092
doi: 10.1016/j.immuni.2018.09.024
Gao, J. et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404 e399 (2016).
pubmed: 27667683
pmcid: 5088716
doi: 10.1016/j.cell.2016.08.069
Chin, Y. E. et al. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science 272, 719–722 (1996).
pubmed: 8614832
doi: 10.1126/science.272.5262.719
Ikeda, H., Old, L. J. & Schreiber, R. D. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev. 13, 95–109 (2002).
pubmed: 11900986
doi: 10.1016/S1359-6101(01)00038-7
Braumuller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013).
pubmed: 23376950
doi: 10.1038/nature11824
Wang, W. et al. CD8
pubmed: 31043744
pmcid: 6533917
doi: 10.1038/s41586-019-1170-y
Kammertoens, T. et al. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature 545, 98–102 (2017).
pubmed: 28445461
pmcid: 5567674
doi: 10.1038/nature22311
Meunier, M. C. et al. T cells targeted against a single minor histocompatibility antigen can cure solid tumors. Nat. Med. 11, 1222–1229 (2005).
pubmed: 16227989
doi: 10.1038/nm1311
Groom, J. R. & Luster, A. D. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol. Cell Biol. 89, 207–215 (2011).
pubmed: 21221121
doi: 10.1038/icb.2010.158
Takeda, K. et al. IFN-gamma is required for cytotoxic T cell-dependent cancer genome immunoediting. Nat. Commun. 8, 14607 (2017).
pubmed: 28233863
pmcid: 5333095
doi: 10.1038/ncomms14607
Garcia-Diaz, A. et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19, 1189–1201 (2017).
pubmed: 28494868
pmcid: 6420824
doi: 10.1016/j.celrep.2017.04.031
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
pubmed: 12091876
doi: 10.1038/nm730
Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
pubmed: 11015443
pmcid: 2193311
doi: 10.1084/jem.192.7.1027
Pai, C. S. et al. Clonal deletion of tumor-specific T cells by interferon-gamma confers therapeutic resistance to combination immune checkpoint blockade. Immunity 50, 477–492 e478 (2019).
pubmed: 30737146
pmcid: 6886475
doi: 10.1016/j.immuni.2019.01.006
Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 e1512 (2016).
pubmed: 27912061
pmcid: 5385895
doi: 10.1016/j.cell.2016.11.022
Altan-Bonnet, G. & Mukherjee, R. Cytokine-mediated communication: a quantitative appraisal of immune complexity. Nat. Rev. Immunol. 19, 205–217 (2019).
pubmed: 30770905
doi: 10.1038/s41577-019-0131-x
pmcid: 8126146
Huse, M., Lillemeier, B. F., Kuhns, M. S., Chen, D. S. & Davis, M. M. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7, 247–255 (2006).
pubmed: 16444260
doi: 10.1038/ni1304
Helmstetter, C. et al. Individual T helper cells have a quantitative cytokine memory. Immunity 42, 108–122 (2015).
pubmed: 25607461
doi: 10.1016/j.immuni.2014.12.018
Honda, T. et al. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40, 235–247 (2014).
pubmed: 24440150
pmcid: 4792276
doi: 10.1016/j.immuni.2013.11.017
Sanderson, N. S. et al. Cytotoxic immunological synapses do not restrict the action of interferon-gamma to antigenic target cells. Proc. Natl Acad. Sci. USA 109, 7835–7840 (2012).
doi: 10.1073/pnas.1116058109
pubmed: 22547816
pmcid: 3356634
Perona-Wright, G., Mohrs, K. & Mohrs, M. Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nat. Immunol. 11, 520–526 (2010).
pubmed: 20418876
pmcid: 2895995
doi: 10.1038/ni.1866
Müller, A. J. et al. CD4
pubmed: 22727490
doi: 10.1016/j.immuni.2012.05.015
Harris, A. W. et al. The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J. Exp. Med. 167, 353–371 (1988).
pubmed: 3258007
doi: 10.1084/jem.167.2.353
Hart, I. R. The selection and characterization of an invasive variant of the B16 melanoma. Am. J. Pathol. 97, 587–600 (1979).
pubmed: 507192
pmcid: 2042430
Sugiura, K. & Stock, C. C. Studies in a tumor spectrum. I. Comparison of the action of methylbis(2-chloroethyl)amine and 3-bis(2-chloroethyl)aminomethyl-4-methoxymethyl-5-hydroxy-6-methylpyridine on the growth of a variety of mouse and rat tumors. Cancer 5, 382–402 (1952).
pubmed: 14905426
doi: 10.1002/1097-0142(195203)5:2<382::AID-CNCR2820050229>3.0.CO;2-3
Milo, I. et al. The immune system profoundly restricts intratumor genetic heterogeneity. Sci. Immunol. 3, eaat1435 (2018).
pubmed: 30470696
doi: 10.1126/sciimmunol.aat1435
Oyler-Yaniv, J. et al. Catch and release of cytokines mediated by tumor phosphatidylserine converts transient exposure into long-lived inflammation. Mol. Cell 66, 635–647 e637 (2017).
pubmed: 28575659
pmcid: 6611463
doi: 10.1016/j.molcel.2017.05.011
Li, H. et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176, 775–789 e718 (2019).
pubmed: 30595452
doi: 10.1016/j.cell.2018.11.043
Fan, J. et al. Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Nat. Methods 13, 241–244 (2016).
pubmed: 26780092
pmcid: 4772672
doi: 10.1038/nmeth.3734
Kupfer, A., Mosmann, T. R. & Kupfer, H. Polarized expression of cytokines in cell conjugates of helper T cells and splenic B cells. Proc. Natl Acad. Sci. USA 88, 775–779 (1991).
pubmed: 1825141
doi: 10.1073/pnas.88.3.775
pmcid: 50896
Egen, J. G. et al. Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity 34, 807–819 (2011).
pubmed: 21596592
pmcid: 3164316
doi: 10.1016/j.immuni.2011.03.022
Olekhnovitch, R., Ryffel, B., Muller, A. J. & Bousso, P. Collective nitric oxide production provides tissue-wide immunity during leishmania infection. J. Clin. Invest. 124, 1711–1722 (2014).
pubmed: 24614106
pmcid: 3973105
doi: 10.1172/JCI72058
Postat, J., Olekhhnovitch, R., Lemaïtre, F. & Bousso, P. A metabolism-based quorum sensing mechanism contributes to termination of inflammatory responses. Immunity 49, 654–665 (2018).
pubmed: 30266340
doi: 10.1016/j.immuni.2018.07.014
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 46, 609–620 (2017).
pubmed: 28389069
pmcid: 5442880
doi: 10.1016/j.immuni.2017.03.011
Stahl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).
pubmed: 27365449
doi: 10.1126/science.aaf2403
Shah, S., Lubeck, E., Zhou, W. & Cai, L. seqFISH accurately detects transcripts in single cells and reveals robust spatial organization in the hippocampus. Neuron 94, 752–758 e751 (2017).
doi: 10.1016/j.neuron.2017.05.008
pubmed: 28521130
Wang, X. et al. Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361, pii: eaat5691 (2018).
doi: 10.1126/science.aat5691
Cazaux, M. et al. Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity. J. Exp. Med. 216, 1038–1049 (2019).
pubmed: 30936262
pmcid: 6504219
doi: 10.1084/jem.20182375
Vincent, L. Morphological grayscale reconstruction in image analysis: applications and efficient algorithms. IEEE Trans. Image Process. 2, 176–201 (1993).
pubmed: 18296207
doi: 10.1109/83.217222
Janky, R. et al. iRegulon: from a gene list to a gene regulatory network using large motif and track collections. PLoS Comput. Biol. 10, e1003731 (2014).
pubmed: 25058159
pmcid: 4109854
doi: 10.1371/journal.pcbi.1003731
Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70–80 (2018).
doi: 10.1038/nbt.4038
pubmed: 29227469
McInnes, L., Healy, J. & Melville, J. UMAP: uniform manifold approximation and projection for dimension reduction. Preprint at arXiv https://arxiv.org/abs/1802.03426 (2018).