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Pitt J.M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Pitt J.M.,French Institute of Health and Medical Research | Pitt J.M.,University Paris - Sud | Andre F.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 14 more authors.
Journal of Clinical Investigation | Year: 2016

DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell-dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell-based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.

Pitt J.M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Pitt J.M.,French Institute of Health and Medical Research | Pitt J.M.,University Paris - Sud | Kroemer G.,French Institute of Health and Medical Research | And 6 more authors.
Journal of Clinical Investigation | Year: 2016

Intercellular signaling via extracellular vesicles (EVs) is an underappreciated modality of cell-cell crosstalk that enables cells to convey packages of complex instructions to specific recipient cells. EVs transmit these instructions through their cargoes of multiple proteins, nucleic acids, and specialized lipids, which are derived from their cells of origin and allow for combinatorial effects upon recipient cells. This Review series brings together the recent progress in our understanding of EV signaling in physiological and pathophysiological conditions, highlighting how certain EVs, particularly exosomes, can promote or regulate infections, host immune responses, development, and various diseases-notably cancer. Given the diverse nature of EVs and their abilities to profoundly modulate host cells, this series puts particular emphasis on the clinical applications of EVs as therapeutics and as diagnostic biomarkers.

Yang H.,University of Paris Descartes | Yang H.,University Pierre and Marie Curie | Yang H.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Yang H.,Peking Union Medical College | And 24 more authors.
Cancer Research | Year: 2015

STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3-/- cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3-/- cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3-/- cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3-/- and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. © 2015 American Association for Cancer Research.

Semeraro M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Semeraro M.,French Institute of Health and Medical Research | Semeraro M.,University Paris - Sud | Rusakiewicz S.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 10 more authors.
OncoImmunology | Year: 2015

Until recently, the pathophysiological impact of natural killer (NK) lymphocytes has been largely elusive. Capitalizing on our previous discovery that NK cells mediate immunosurveillance against gastrointestinal stromal tumors (GISTs), we have now investigated the potential influence of immunostimulatory and immunosuppressive isoforms of the NK receptor NKp30 on the fate of infants with neuroblastoma. In three independent cohorts of high-risk neuroblastoma, we observed a similar prognostic impact of the ratio of immunostimulatory vs. immunosuppressive NKp30 isoforms. Patients with high-risk neuroblastoma that are in remission after induction chemotherapy have a higher risk of relapse if their circulating and bone marrow NK cells express the preponderantly immunosuppressive NKp30 C isoform, as determined by a robust RT-PCR-based assay. We also found that neuroblastoma cells express the NKp30 ligand B7-H6, which can be shed from the tumor cells. Elevated soluble B7-H6 levels contained in patient sera inhibited NK functions in vitro and correlated with downregulation of NK-p30 on NK cells, as well as with bone marrow metastasis and chemoresistance. Altogether, these results support the contention that NK cells play a decisive role in the immunosurveillance of neuroblastoma. In light of these results, efforts should be undertaken to investigate NK cell functions in all major cancer types, with the obvious expectation of identifying additional NK cell-related prognostic or predictive biomarkers and improving NK cell based immunotherapeutic strategies against cancer. © 2015, Taylor & Francis Group, LLC.

Yang H.,French Institute of Health and Medical Research | Yang H.,University of Paris Descartes | Yang H.,University Pierre and Marie Curie | Yang H.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 47 more authors.
OncoImmunology | Year: 2016

Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3−/− and Mlkl−/− tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3−/− and Mlkl−/− cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity. © 2016 Taylor & Francis Group, LLC.

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