IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells

Fisher, Daniel; Chen, Qing; Skitzki, Joseph J.; Muhitch, Jason B.; Zhou, Lei; Appenheimer, Michelle M.; Vardam, Trupti D.; Weis, Emily; Passanese, Jessica; Wang, Wan‐Chao; Gollnick, Sandra O.; Dewhirst, Mark W.; Rose-John, Stefan; Repasky, Elizabeth A.; Baumann, Heinz; Evans, Sharon S.

doi:10.1172/jci44952

Cited by 212 publications

(343 citation statements)

References 74 publications

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“…Many types of tumors can actively prevent T-cell infiltration by modifying gene expression of adhesion molecules such as ICAM-1 and VCAM-1 in vascular endothelial cells (21) or by inducing posttranslational modification of local chemokine signals, including CCL2 (23). Our data are in agreement with several strategies that have been proposed to optimize antitumor T-cell migration by transducing highly targeted, localized chemokine signals at the tumor site.…”

Section: Discussionsupporting

confidence: 88%

“…For example, monitoring of transferred CTLs after ACT has shown that most infused CD8 + T cells localize to the lung, liver, or spleen, whereas only ∼1% of the total transferred T cells migrate to the tumor (3,20). In addition, the majority of adoptively transferred CD8 + T cells are preferentially found in the tumor periphery allowing time for escape mechanisms to be enacted in the central regions of the tumor (21,22). In this study, we developed a photoactivatable chemokine receptor that leverages common structure-function relationships between two different GPCR families (rhodopsin receptor and chemokine receptor).…”

Section: Discussionmentioning

confidence: 99%

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Optogenetic control of chemokine receptor signal and T-cell migration

Hyun

Lim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Precise regulation of chemokine signal is critical for directional migration of cells. In the study of complex cell behavior, it remains difficult to manipulate chemokine activity at precise times and places within living animals, and it is not possible to study different chemokine effects on defined cell types over a range of timescales. Furthermore, a given chemokine can activate multiple chemokine receptors and vice versa. Here we developed a photoactivatable chemokine receptor that can induce highly specific chemokine signals and guide cell migration toward the light stimulation. This work will advance our understanding of the cell migration process with a number of previously unidentified findings. Clinically, our photoactivatable chemokine receptor approach may have broad applications for adoptive cell transfer therapy.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Optogenetic control of chemokine receptor signal and T-cell migration

Hyun

Lim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In line with this theory, our laboratory and that of others, have long been interested in the positive effects of temporarily inducing a mild (fever range, ∼39°C) hyperthermia on various immune cells in mice (32), where (unlike the experiments reported here) body temperature is transiently elevated for several hours. Because short-term mild hyperthermia causes a similar increase of CD8 + T cells and a decrease of T reg cells (32,33) in the tumor microenvironment, an open question is whether these therapeutically beneficial effects are functionally linked to alleviation of cold stress.…”

Section: Discussionmentioning

confidence: 99%

Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature

Kokolus¹,

Capitano²,

Lee³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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275

288

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We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20-26°C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30-31°C), we observe a striking reduction in tumor formation, growth rate and metastasis. This improved control of tumor growth is dependent upon the adaptive immune system. We observe significantly increased numbers of antigen-specific CD8 + T lymphocytes and CD8 + T cells with an activated phenotype in the tumor microenvironment at thermoneutrality. At the same time there is a significant reduction in numbers of immunosuppressive MDSCs and regulatory T lymphocytes. Notably, in temperature preference studies, tumor-bearing mice select a higher ambient temperature than non-tumor-bearing mice, suggesting that tumor-bearing mice experience a greater degree of coldstress. Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response. murine tumor models | metabolism

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“…Specifically, the expression of the glycoprotein intracellular adhesion molecule 1 (ICAM-1) is increased via heat-induced increased interleukin 6 (IL-6) signalling. ICAM-1 then attracts effector/ memory T-cells [69,75,76]. Hyperthermia not only alters expression of vascular adhesion molecules, but also induces an increased expression of surface molecules on tumour cells.…”

Section: The Immune System and Hyperthermiamentioning

confidence: 99%

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

Tempel¹,

Horsman

Kanaar³

2016

International Journal of Hyperthermia

102

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It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia. Therefore, we are now at a juncture where the parameters that will influence the efficacy of hyperthermia in cancer treatment can be optimised in a more systematic and rational manner. In addition, the novel insights in hyperthermia's many biological effects on tumour cells will ultimately result in new treatment regimes. For example, the molecular effects of hyperthermia on the essential cellular process of DNA repair suggest novel combination therapies, with DNA damage response targeting drugs that should now be clinically explored. Here, we provide an overview of recent studies on the various macroscopic and microscopic biological effects of hyperthermia. We indicate the significance of these effects on current treatments and suggest how they will help design novel future treatments. ARTICLE HISTORY

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IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells

Cited by 212 publications

References 74 publications

Optogenetic control of chemokine receptor signal and T-cell migration

Optogenetic control of chemokine receptor signal and T-cell migration

Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

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