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Tumour ischaemia by interferon-? resembles physiological blood vessel regression.

ABSTRACT: The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-? (IFN?) is critical in most of the analysed models. Although IFN? can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFN? and by which mechanism IFN? contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFN? induction and an IFN?-GFP fusion protein in large, vascularized tumours growing in mice that express the IFN? receptor exclusively in defined cell types. Responsiveness to IFN? by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFN?-induced tumour regression, whereas responsiveness of endothelial cells to IFN? was necessary and sufficient. Intravital microscopy revealed IFN?-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFN?-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFN?-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.

SUBMITTER: Kammertoens T

PROVIDER: S-EPMC5567674 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Tumour ischaemia by interferon-γ resembles physiological blood vessel regression.

Kammertoens Thomas T Friese Christian C Arina Ainhoa A Idel Christian C Briesemeister Dana D Rothe Michael M Ivanov Andranik A Szymborska Anna A Patone Giannino G Kunz Severine S Sommermeyer Daniel D Engels Boris B Leisegang Matthias M Textor Ana A Fehling Hans Joerg HJ Fruttiger Marcus M Lohoff Michael M Herrmann Andreas A Yu Hua H Weichselbaum Ralph R Uckert Wolfgang W Hübner Norbert N Gerhardt Holger H Beule Dieter D Schreiber Hans H Blankenstein Thomas T

Nature 20170426 7652

The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we ...[more]

PMID: 28445461

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Project description:PD-1 immune checkpoint blockade against inhibitory receptors such as receptor programmed cell death-1 (PD-1), has revolutionized cancer treatment. Effective immune reactivity against tumour antigens requires the infiltration and activation of tumour-infiltrating T-cells (TILs). In this context, ligation of the antigen-receptor complex (TCR) in combination with the co-receptor CD28 activates the intracellular mediator AKT (or PKB, protein kinase B) and its downstream targets. PD-1 inhibits the activation of AKT/PKB. Given this, we assessed whether the direct activation of AKT might be effective in activating the immune system to limit the growth of tumors that are resistant to PD-1 checkpoint blockade. We found that the small molecule activator of AKT (SC79) limited growth of a B16 tumor and an EMT-6 syngeneic breast tumor model that are poorly responsive to PD-1 immunotherapy. In the case of B16 tumors, direct AKT activation induced (i) a reduction of suppressor regulatory (Treg) TILs and (ii) an increase in effector CD8+ TILs. SC79 in vivo therapy caused a major increase in the numbers of CD4+ and CD8+ TILs to express interferon-γ (IFN-γ). This effect on IFN-γ expression distinguished responsive from non-responsive anti-tumor responses and could be recapitulated ex vivo with human T-cells. In CD4+FoxP3+Treg TILs, AKT induced IFN-γ expression was accompanied by a loss of suppressor activity, the conversation to CD4+ helper Th1-like TILs and a marked reduction in phospho-SHP2. In CD8+ TILs, we observed an increase in the phospho-activation of PLC-γ. Further, the genetic deletion of the transcription factor T-bet (Tbx21) blocked the increased IFN-γ expression on all subsets while ablating the therapeutic benefits of SC79 on tumor growth. Our study shows that AKT activation therapy acts to induce IFN-γ on CD4 and CD8 TILs that is accompanied by the intra-tumoral conversation of suppressive Tregs into CD4+Th1-like T-cells and augmented CD8 responses.

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Tumour ischaemia by interferon-? resembles physiological blood vessel regression.

Publications

Tumour ischaemia by interferon-γ resembles physiological blood vessel regression.

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