Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy

Kallert, Sandra M.; Darbre, Stéphanie; Bonilla, Weldy V.; Kreutzfeldt, Mario; Pagé, Nicolas; Müller, Philipp; Kreuzaler, Matthias; Lu, Min; Favre, Stéphanie; Kreppel, Florian; Löhning, Max; Luther, Sanjiv A.; Zippelius, Alfred; Merkler, Doron; Pinschewer, Daniel D.

doi:10.1038/ncomms15327

Cited by 71 publications

(136 citation statements)

References 69 publications

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“…IL-33 could also indirectly activate effector T cells. For instance, a replicating viral vector system used in cancer immunotherapy which delivers tumor-associated antigens to DC for efficient cytotoxic T cells priming, depends on IL-33 signaling ( 129 ). IL-33 could likewise increase T cell activation to promote graft- vs.-leukemia (GVL) reactions while decreasing fatal graft-vs.-host- disease (GVHD) ( 130 ).…”

Section: Discussionmentioning

confidence: 99%

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

Fournié

Poupot

2018

Front. Immunol.

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Interleukin-33 (IL-33), considered as an alarmin released upon tissue stress or damage, is a member of the IL-1 family and binds the ST2 receptor. First described as a potent initiator of type 2 immune responses through the activation of T helper 2 (TH2) cells and mast cells, IL-33 is now also known as an effective stimulator of TH1 immune cells, natural killer (NK) cells, iNKT cells, and CD8 T lymphocytes. Moreover, IL-33 was shown to play an important role in several cancers due to its pro and anti-tumorigenic functions. Currently, IL-33 is a possible inducer and prognostic marker of cancer development with a direct effect on tumor cells promoting tumorigenesis, proliferation, survival, and metastasis. IL-33 also promotes tumor growth and metastasis by remodeling the tumor microenvironment (TME) and inducing angiogenesis. IL-33 favors tumor progression through the immune system by inducing M2 macrophage polarization and tumor infiltration, and upon activation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) or regulatory T cells. The anti-tumor functions of IL-33 also depend on infiltrated immune cells displaying TH1 responses. This review therefore summarizes the dual role of this cytokine in cancer and suggests that new proposals for IL-33-based cancer immunotherapies should be considered with caution.

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Section: Discussionmentioning

confidence: 99%

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

Fournié

Poupot

2018

Front. Immunol.

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“…Recombinant LCMV strains were generated according to established methods (Kallert et al, 2017;Kreutzfeldt et al, 2013). The following virus strains were used: recombinant LCMV encoding for the glycoprotein of vesicular stomatitis virus (VSV) instead of its own glycoprotein (rLCMV/ INDG, abbreviated rLCMV throughout); rLCMV encoding for Cre recombinase (rLCMV-Cre); LCMVwt (Armstrong strain).…”

Section: Virus Infectionmentioning

confidence: 99%

Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping

Liberto

Pantelyushin

Kreutzfeldt

et al. 2018

Cell

Self Cite

147

137

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Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for aberrant synaptic connectivity in the context of CD8 T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8 T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen's encephalitis patients. In this devastating CD8 T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8 T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.

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“…S1A ). Systemic infection with lymphocytic choriomeningitis virus (LCMV)-OVA, a replication-competent, attenuated LCMV mutant expressing ovalbumin (OVA) as model antigen ( 33 ), led to transient and low viral titers in spleen on day 3 p.i. that remained below the detection limit in PLN and SMG ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…transferred into recipient mice 24 h before i.p. infection with 10 5 pfu LCMV-OVA ( 33 ). Experimental read-outs for the acute, cleared and memory phase of viral infection were performed 6, 15 and ≥ 30 days p.i., respectively.…”

Section: Methodsmentioning

confidence: 99%

Salivary gland macrophages assist tissue-resident CD8⁺T cell immune surveillance

Stolp

Thelen

Ficht

et al. 2019

Preprint

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31 32 One sentence summary 33 Combined in vitro and in vivo imaging of salivary gland-resident tissue memory CD8 + T cells (TRM) uncovers 34 their unique migratory behavior and describes a novel accessory function of tissue macrophages to assist TRM 35 surveillance. 36 Abstract 37Tissue macrophages and tissue resident memory CD8 + T cells (TRM) play important roles for pathogen sensing 38 and rapid protection of barrier tissues. To date, it is incompletely understood how these two cell types 39 cooperate for efficient organ surveillance during homeostasis. Here, we used intravital imaging to show that 40 TRM dynamically crawled along tissue macrophages in murine submandibular salivary glands (SMG) during 41 the memory phase following a viral infection. Ex vivo confined SMG TRM integrated an unexpectedly wide 42 range of migration modes: in addition to chemokine-and adhesion receptor-driven motility, SMG TRM 43 displayed a remarkable capacity of autonomous motility in the absence of chemoattractants and adhesive 44 ligands. This unique intrinsic SMG TRM motility was transmitted by friction and adaptation to 45 microenvironmental topography through protrusion insertion into permissive gaps. Analysis of extracellular 46 space in SMG using super-resolution shadow imaging showed discontinuous attachment of tissue 47 macrophages to neighboring epithelial cells, offering paths of least resistance for patrolling TRM. Upon tissue 48 macrophage depletion, intraepithelial SMG TRM showed decreased motility and reduced epithelial crossing 49 events, and failed to cluster in response to local inflammatory chemokine stimuli. In sum, our data uncover 50 a continuum of SMG TRM migration modes and identify a new accessory function of tissue macrophages to 51 facilitate TRM patrolling of the complex exocrine gland architecture. 52 53

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Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy

Cited by 71 publications

References 69 publications

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping

Salivary gland macrophages assist tissue-resident CD8⁺T cell immune surveillance

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Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy

Cited by 71 publications

References 69 publications

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping

Salivary gland macrophages assist tissue-resident CD8+T cell immune surveillance

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Salivary gland macrophages assist tissue-resident CD8⁺T cell immune surveillance