Tumor immune escape by the loss of homeostatic chemokine expression

Pivarcsi, Andor; Müller, Anja; Hippe, Andreas; Rieker, Juliane; Lierop, Anke Van; Steinhoff, Martin; Seeliger, Stephan; Kubitza, Robert; Pippirs, U.; Meller, Stephan; Gerber, Peter Arne; Liersch, Rüediger; Buenemann, Erich; Sonkoly, Enikö; Wiesner, Ulrike; Hoffmann, Thomas; Schneider, L; Piekorz, Roland P.; Enderlein, Elaine; Reifenberger, Julia; Rohr, Ulrich-Peter; Haas, Rainer; Boukamp, Petra; Haase, Ingo; Nürnberg, Bernd; Ruzicka, Thomas; Zlotnik, Albert; Homey, Bernhard

doi:10.1073/pnas.0705673104

Cited by 123 publications

(109 citation statements)

References 30 publications

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“…The expression of chemokine or chemokine receptors may lead to immune tolerance or immune escape, which may, in turn, result in tumor progression. 45,47,48 Our data suggest that decreased interactions between CCR7/CCL21, CCR10/CCL27 and CCL28 may play an important role in CSC-DC vaccinationinduced inhibition of tumor metastasis. We previously reported that blockade of the IL-8 receptor CXCR1 selectively depleted the CSC population.…”

Section: Discussionmentioning

confidence: 92%

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

et al. 2015

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Keywords: antitumor immunity, cancer stem cell, dendritic cell, metastasis, vaccine Abbreviations: ALDH, aldehyde dehydrogenase; CSC, cancer stem cell; CSC-DC, CSC lysate-pulsed dendritic cell; DC, dendritic cell; H-DC, heterogeneous, unsorted tumor cell lysate-pulsed dendritic cell; RT, radiation therapy; qRT-PCR, real time quantitative PCR.The inability to target cancer stem cells (CSC) may be a significant factor contributing to treatment failure. We have developed a strategy to target the CSC populations in melanoma and squamous cell carcinoma using CSC lysate-pulsed dendritic cells (DCs). The CSC-DC vaccine was administered in the adjuvant setting after localized radiation therapy of established tumors. Using mouse models we demonstrated that DCs pulsed with CSCs enriched by virtue of their expression of the CSC marker ALDH (termed CSC-DC) significantly inhibited tumor growth, reduced development of pulmonary metastases and prolonged survival. The effect was associated with downregulation of chemokine (C-C motif) receptors CCR7 and CCR10 in tumor cells and decreased expression of the chemokine (C-C motif) ligands CCL21, CCL27 and CCL28 in lung tissue. The CSC-DC vaccine significantly reduced ALDH high CSC frequency in primary tumors. Direct targeting of CSCs was demonstrated by the specific binding of IgG produced by ALDH high CSC-DC vaccineprimed B cells to ALDH high CSCs, resulting in lysis of these target CSCs in the presence of complement. These data suggest that the CSC-DC vaccine approach may be useful in the adjuvant setting where local and systemic relapse are high after conventional treatment of cancers.

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Section: Discussionmentioning

confidence: 92%

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

et al. 2015

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“…This is in line with our results showing altered expression of chemokines during the transformation process. Indeed, keratinocytes from human skin tumors exhibited reduced expression of CCL27, a potent attractor of T cells toward the skin (18). Apart from reduced expression during malignant transformation, intratumoral chemokines can also be modified by peroxynitrites, which leads to defective recruitment of T cells to tumor islets (19).…”

Section: Discussionmentioning

confidence: 99%

Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors

Salmon

Franciszkiewicz²,

Damotte³

et al. 2012

J. Clin. Invest.

806

699

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Appropriate localization and migration of T cells is a prerequisite for antitumor immune surveillance. Studies using fixed tumor samples from human patients have shown that T cells accumulate more efficiently in the stroma than in tumor islets, but the mechanisms by which this occurs are unknown. By combining immunostaining and real-time imaging in viable slices of human lung tumors, we revealed that the density and the orientation of the stromal extracellular matrix likely play key roles in controlling the migration of T cells. Active T cell motility, dependent on chemokines but not on β1 or β2 integrins, was observed in loose fibronectin and collagen regions, whereas T cells migrated poorly in dense matrix areas. Aligned fibers in perivascular regions and around tumor epithelial cell regions dictated the migratory trajectory of T cells and restricted them from entering tumor islets. Consistently, matrix reduction with collagenase increased the ability of T cells to contact cancer cells. Thus, the stromal extracellular matrix influences antitumor immunity by controlling the positioning and migration of T cells. Understanding the mechanisms by which this collagen network is generated has the potential to aid in the development of new therapeutics.

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“…In the tumor cells themselves, antiapoptotic molecules and cytotoxic determinants are upregulated, whereas the Ag-presentation molecule, MHC, is downregulated; moreover, HCC cells secrete various immunosuppressive cytokines, including VEGF, IL-10, and TGF-b (32,33). Among these, IL-10 and TGF-boften produced abundantly in cancer patients-are potent immune suppressors that negatively regulate NK cell function (34,35).…”

Section: Discussionmentioning

confidence: 99%

NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma

Sui

Zhang

Sun

et al. 2014

The Journal of Immunology

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STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell–deficient nude mice, a unique NK cell–mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-β cytokines were reduced in mice bearing STAT3-blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo.

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Tumor immune escape by the loss of homeostatic chemokine expression

Cited by 123 publications

References 30 publications

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors

NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma

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