Immune cells participate in the oncosuppressive activity of parvovirus H-1PV and are activated as a result of their abortive infection with this agent

Grekova, Svitlana P.; Aprahamian, Marc; Giese, Nathalia A.; Schmitt, Steffen; Giese, Thomas; Falk, Christine S.; Daeffler, Laurent; Cziepluch, Celina; Rommelaere, Jean; Raykov, Zahari

doi:10.4161/cbt.10.12.13455

Cited by 39 publications

(57 citation statements)

References 27 publications

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“…That they might pass the job on to the immune system is actually expected, because a productive lytic viral infection of cancer cells should promote the display or release of both tumorassociated antigens and immunostimulating viral or cellular molecular patterns. Adoptive transfer, rechallenge, and immunodepletion experiments indicate that the host immune system takes part in PV-mediated oncosuppression (41,42). The active role of PVs in inducing this anticancer immune response is further supported by the observation that PV infection of tumor cells enhances their ability to serve as an autologous vaccine (42,43) and to stimulate both natural killer (44) and dendritic (45) cells with which they come into contact.…”

Section: Cell Disturbances and Pv Oncolysismentioning

confidence: 74%

“…The ability of PVs to act as adjuvants to boost the host antitumor response can also be increased by arming them with immunostimulatory molecular patterns (43). Furthermore, PVs can be combined with ionizing radiation (58), the cytostatic drug gemcitabine (53), the cytokine IFN-g (41), or oncolytic reovirus (59) to achieve additive or even synergistic therapeutic effects. Indeed, the non-PV component of these combination treatments can be administered so as to minimize interference with PV replication and instead potentiate PV oncolytic or immunomodulating activities.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Nüesch

Lacroix

Marchini

et al. 2012

Clinical Cancer Research

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Rodent parvoviruses (PV) are recognized for their intrinsic oncotropism and oncolytic activity, which contribute to their natural oncosuppressive effects. Although PV uptake occurs in most host cells, some of the subsequent steps leading to expression and amplification of the viral genome and production of progeny particles are upregulated in malignantly transformed cells. By usurping cellular processes such as DNA replication, DNA damage response, and gene expression, and/or by interfering with cellular signaling cascades involved in cytoskeleton dynamics, vesicular integrity, cell survival, and death, PVs can induce cytostasis and cytotoxicity. Although productive PV infections normally culminate in cytolysis, virus spread to neighboring cells and secondary rounds of infection, even abortive infection or the sole expression of the PV nonstructural protein NS1, is sufficient to cause significant tumor cell death, either directly or indirectly (through activation of host immune responses). This review highlights the molecular pathways involved in tumor cell targeting by PVs and in PV-induced cell death. It concludes with a discussion of the relevance of these pathways to the application of PVs in cancer therapy, linking basic knowledge of PV-host cell interactions to preclinical assessment of PV oncosuppression. Clin Cancer Res; 18(13); 3516-23. Ó2012 AACR.

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Section: Cell Disturbances and Pv Oncolysismentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Nüesch

Lacroix

Marchini

et al. 2012

Clinical Cancer Research

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“…3 H-1PV is considered oncotropic, efficiently infecting transformed human cell lines and human tumor cells, including melanoma, hepatoma, colon and gastric cancer cells [4][5][6] ; however, in contrast to these fast replicating cells, human immune cells and primary hepatocytes are not infected or lysed. 4,5,7 It was reported that H-1PV can also replicate in humans after injection without causing severe adverse reactions. 8,9 H-1PV has oncotropic and oncolytic properties and was shown to trigger oncosuppressive effects against different malignancies.…”

mentioning

confidence: 99%

“…This is based on the immunostimulating activity of PVs which is also apparent from the H-1PV/TCL-induced activation of NK cells, the adjuvant effect of H-1PV on an autologous tumor cell vaccine and the Th1-based immune upregulation achieved by H-1PV in rats and human PBMCs. 7,[22][23][24] Furthermore, the death mechanisms activated by PVs allow them to circumvent resistance of tumor cells to conventional death inducers 10,25 and preclinical data on efficacy and safety produced proofs of concept leading to the recent launching of a phase I/IIa clinical trial. 26 Dendritic cells play an important role in this, linking the innate with adaptive immune responses.…”

mentioning

confidence: 99%

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

Sieben

Schäfer-Keller

Dinsart

et al. 2012

Intl Journal of Cancer

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This study aimed to investigate the function of toll-like receptors (TLRs) during oncolytic parvovirus H-1 (H-1PV)-induced human immune responses. First, the role of TLRs in the activation of the NFjB transcription factor was characterized; second, the immunologic effects of H-1PV-induced tumor cell lysates (TCL) on human antitumor immune responses were evaluated. A human ex vivo model was used to study immune responses with dendritic cells (DCs). Human embryonic kidney cells (HEK293) transfected to stably express TLRs were used as potential human DC equivalents to further investigate the role of specific TLRs during immune activation. TLR3 and TLR9 were activated by H-1PV infection, which correlated with NFjB translocation to the nucleus and a reduced cytoplasmic IjB expression. Using a TLR-signaling reporter plasmid (pNiFty-Luc), NFjB activity was increased following H-1PV infection. In addition, human DCs coincubated with H-1PV-induced TCL demonstrated increased TLR3 and TLR9 expression. These data suggest that H-1PV-induced TCL stimulate human DCs at least in part through TLR-dependent signaling pathways. Thus, DC maturation occurred through exposure to H-1PV-induced TCL through TLR-signaling leading to NFjB-dependent activation of the adaptive immune system as indicated by the increased expression of CD86, TLR3 and TLR9. Furthermore, the transcription of various cytokines indicates the activation of immune response, therefore the production of the proinflammatory cytokine TNF-a was determined. Here, H-1PV-induced TCL significantly enhanced the TNF-a level by DCs after coculture. H-1PV oncolytic virotherapy enhances immune priming by different effects on DCs and generates antitumor immunity. These findings potentially offer a new approach to tumor therapy.

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“…H-1PV is highly efficient in eliminating PDAC cells, and its action is greatly enhanced by gemcitabine (32,33). The combination of in vitro experiments, studies in immunodeficient mice with human xenografts, and studies in immunocompetent rat models showed that the anticancer protection comprises cytoreductive and immune-mediated components, with gamma interferon (IFN-␥) emerging as a critical end effector (34)(35)(36). Yet the mechanism underlying the induction of the immune reaction remains obscure.…”

mentioning

confidence: 99%

Complementary Induction of Immunogenic Cell Death by Oncolytic Parvovirus H-1PV and Gemcitabine in Pancreatic Cancer

Angelova

Grekova

Heller

et al. 2014

J Virol

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease, with a median survival time of less than 9 months and a 5-year survival rate of Ͻ1%. Current advances in surgical, (neo)adjuvant, and palliative treatments have failed to prevent recurrence and ultimate metastasis (1-3).In order to be effective, chemotherapy must reduce the tumor burden, promote anticancer immunity, and alleviate intratumoral immunosuppression (4-6). Forced tumor cell death in an immunogenic manner (i.e., immunogenic cell death [ICD]) has been proposed as the best way to trigger an adaptive immune response, boosting the therapeutic efficacy of a cytoreductive treatment (7,8). Preapoptotic surface exposure of calreticulin (CRT) (as a result of the endoplasmic reticulum stress response), as well as release of ATP (autophagy) and high-mobility group box B1 protein (HMGB1) (late apoptosis/necrosis), is considered the optimal ICD combination for dying tumor cells to enable paracrine activation of dendritic cells and the consequent priming of cytotoxic effectors. The surface exposure of CRT promotes uptake of dying tumor cells by dendritic cells, and the release of HMGB1 engages

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Immune cells participate in the oncosuppressive activity of parvovirus H-1PV and are activated as a result of their abortive infection with this agent

Cited by 39 publications

References 27 publications

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

Complementary Induction of Immunogenic Cell Death by Oncolytic Parvovirus H-1PV and Gemcitabine in Pancreatic Cancer

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