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Ladoire Immune

C Mirjolet, C Charon-Barra, S Ladoire, F Arbez-Gindre, A Bertaut, F Ghiringhelli, A Leroux, D Peiffert, C Borg, J F Bosset, G Créhange
Introduction: Some studies have suggested that baseline tumor-infiltrating-lymphocytes (TILs), such as CD8+ and FoxP3+ T-cells, may be associated with a better prognosis in colorectal cancer. We sought to investigate modulation of the immune response by preoperative radiotherapy (preopRT) and its impact on survival in locally advanced rectal cancer (LARC). Materials & Methods: We analyzed data for 237 patients with LARC who received RT. Density of TILS (CD8+ and FoxP3+) in intraepithelial (iTILs) and stromal compartments (sTILs) were evaluated from surgery pathological specimens and biopsies performed at baseline...
2018: Oncoimmunology
Etienne Humblin, Marion Thibaudin, Fanny Chalmin, Valentin Derangère, Emeric Limagne, Corentin Richard, Richard A Flavell, Sandy Chevrier, Sylvain Ladoire, Hélène Berger, Romain Boidot, Lionel Apetoh, Frédérique Végran, François Ghiringhelli
Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+ T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression...
December 12, 2017: Nature Communications
Courèche-Guillaume Kaderbhai, Corentin Richard, Jean David Fumet, Anne Aarnink, Sandra Ortiz-Cuaran, Maurice Pérol, Pascal Foucher, Bruno Coudert, Laure Favier, Aurélie Lagrange, Emeric Limagne, Romain Boidot, Sylvain Ladoire, Michel Poudenx, Marius Ilie, Paul Hofman, Pierre Saintigny, François Ghiringhelli
Nivolumab, an anti PD-1 checkpoint inhibitor has demonstrated efficacy in metastatic non-small-cell lung cancer (NSCLC) patients after failure to standard chemotherapy. Standard chemotherapy agents could promote antitumor immune response. We thus examined whether the response to first line chemotherapy could impact on nivolumab benefit. One hundred and 15 patients with NSCLC were included in this retrospective study from 4 different French centers. Forty-three squamous cell carcinomas (SCC), and 72 non-SCC received nivolumab between 2015 and 2016 (3 mg/kg IV Q2W)...
2017: Oncoimmunology
Rachid Madkouri, Coureche Guillaume Kaderbhai, Aurélie Bertaut, Caroline Truntzer, Julie Vincent, Marie Hélene Aubriot-Lorton, Walid Farah, Emeric Limagne, Sylvain Ladoire, Romain Boidot, Valentin Derangère, François Ghiringhelli
BACKGROUND: Interest is growing on immune cells involvement in central nervous system tumors such as glioblastoma. Even if a few reports highlighted that immune classifications could have a prognostic value, no paradigm has been clearly yet established on large and homogeneous cohorts. The aim of our study was to analyze the prognostic role of the in situ immune response of cytotoxic T cells (i.e., CD8(+)), Foxp3 cells, Th17 and tumor-associated macrophages in glioblastoma on two independent large and homogeneous cohorts...
2017: Oncoimmunology
Sylvain Ladoire, Valentin Derangère, Laurent Arnould, Marion Thibaudin, Bruno Coudert, Veronique Lorgis, Isabelle Desmoulins, Marie Chaix, Pierre Fumoleau, François Ghiringhelli
The role of the immune response in breast cancer is now well recognized and increasingly taken in account. The goal of this article is, in the first part, to underline its prognostic impact and to precise the immunosurvelliance, immunoselection and the immunosubversion concepts involved in the control and evasion of breast carcinoma. In the second part, therapeutic strategies for the restauration of anti-tumor immunity are developed. Vaccination strategies and checkpoints inhibitors blockade strategies are discussed as well as the immunogenic death linked to the conventional treatments of breast cancer...
February 2017: Annales de Pathologie
Emeric Limagne, Romain Euvrard, Marion Thibaudin, Cédric Rébé, Valentin Derangère, Angélique Chevriaux, Romain Boidot, Frédérique Végran, Nathalie Bonnefoy, Julie Vincent, Leila Bengrine-Lefevre, Sylvain Ladoire, Dominique Delmas, Lionel Apetoh, François Ghiringhelli
Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX-bevacizumab), as compared with 20 healthy volunteers...
September 15, 2016: Cancer Research
Sylvain Ladoire, Laura Senovilla, David Enot, François Ghiringhelli, Vichnou Poirier-Colame, Kariman Chaba, Gulsun Erdag, Jochen T Schaefer, Donna H Deacon, Laurence Zitvogel, Craig L Slingluff, Guido Kroemer
Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2α; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3...
June 2016: Oncoimmunology
Sylvain Ladoire, David Enot, Fabrice Andre, Laurence Zitvogel, Guido Kroemer
It is well established that the anticancer immune response determines the success of anthracycline-based adjuvant chemotherapy of breast cancer. This effect is in part due to the capacity of anthracyclines to induce immunogenic cell death (ICD), a cell death modality that is preceded by autophagy and followed by HMGB1 release. Recent data on 1,798 mammary carcinoma specimens indicate that patients harboring neoplastic cells that lack immunohistochemical signs of autophagy or that have lost HMGB1 expression have indeed a poor prognosis...
February 2016: Oncoimmunology
Audrey Hennequin, Valentin Derangère, Romain Boidot, Lionel Apetoh, Julie Vincent, David Orry, Jean Fraisse, Sylvain Causeret, François Martin, Laurent Arnould, Françoise Beltjens, François Ghiringhelli, Sylvain Ladoire
Tumor-infiltrating T and B lymphocytes could have the potential to affect cancer prognosis. The objective of this study was to investigate the prognostic significance of tumor infiltration by CD8 and CD4 T cells, and B lymphocytes in patients with localized gastric cancer. In a retrospective cohort of 82 patients with localized gastric cancer and treated by surgery we quantitatively assessed by immunohistochemistry on surgical specimen, immune infiltrates of IL-17(+), CD8(+), Foxp3(+), Tbet(+) T cells and CD20(+) B cells both in the tumor core and at the invasive margin via immunohistochemical analyses of surgical specimens...
February 2016: Oncoimmunology
Sylvain Ladoire, David Enot, Laura Senovilla, François Ghiringhelli, Vichnou Poirier-Colame, Kariman Chaba, Michaela Semeraro, Marie Chaix, Frédérique Penault-Llorca, Laurent Arnould, Marie Laure Poillot, Patrick Arveux, Suzette Delaloge, Fabrice Andre, Laurence Zitvogel, Guido Kroemer
Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact...
May 3, 2016: Autophagy
Marion Thibaudin, Marie Chaix, Romain Boidot, Frédérique Végran, Valentin Derangère, Emeric Limagne, Hélène Berger, Sylvain Ladoire, Lionel Apetoh, François Ghiringhelli
Th17 cells contribute to the development of some autoimmune and allergic diseases by driving tissue inflammation. However, the function of Th17 cells during cancer progression remains controversial. Here, we show that human memory CD25(high) Th17 cells suppress T cell immunity in breast cancer. Ectonucleotidase-expressing Th17 cells accumulated in breast cancer tumors and suppressed CD4(+) and CD8(+) T cell activation. These cells expressed both Rorγt and Foxp3 genes and secreted Th17 related cytokines. We further found that CD39 ectonucleotisase expression on tumor-infiltrating Th17 cells was driven by TGF-βand IL-6...
2016: Oncoimmunology
Erika Vacchelli, Yuting Ma, Elisa E Baracco, Antonella Sistigu, David P Enot, Federico Pietrocola, Heng Yang, Sandy Adjemian, Kariman Chaba, Michaela Semeraro, Michele Signore, Adele De Ninno, Valeria Lucarini, Francesca Peschiaroli, Luca Businaro, Annamaria Gerardino, Gwenola Manic, Thomas Ulas, Patrick Günther, Joachim L Schultze, Oliver Kepp, Gautier Stoll, Céline Lefebvre, Claire Mulot, Francesca Castoldi, Sylvie Rusakiewicz, Sylvain Ladoire, Lionel Apetoh, José Manuel Bravo-San Pedro, Monica Lucattelli, Cécile Delarasse, Valérie Boige, Michel Ducreux, Suzette Delaloge, Christophe Borg, Fabrice André, Giovanna Schiavoni, Ilio Vitale, Pierre Laurent-Puig, Fabrizio Mattei, Laurence Zitvogel, Guido Kroemer
Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity...
November 20, 2015: Science
L Apetoh, S Ladoire, G Coukos, F Ghiringhelli
Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies...
September 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Antonella Sistigu, Takahiro Yamazaki, Erika Vacchelli, Kariman Chaba, David P Enot, Julien Adam, Ilio Vitale, Aicha Goubar, Elisa E Baracco, Catarina Remédios, Laetitia Fend, Dalil Hannani, Laetitia Aymeric, Yuting Ma, Mireia Niso-Santano, Oliver Kepp, Joachim L Schultze, Thomas Tüting, Filippo Belardelli, Laura Bracci, Valentina La Sorsa, Giovanna Ziccheddu, Paola Sestili, Francesca Urbani, Mauro Delorenzi, Magali Lacroix-Triki, Virginie Quidville, Rosa Conforti, Jean-Philippe Spano, Lajos Pusztai, Vichnou Poirier-Colame, Suzette Delaloge, Frederique Penault-Llorca, Sylvain Ladoire, Laurent Arnould, Joanna Cyrta, Marie-Charlotte Dessoliers, Alexander Eggermont, Marco E Bianchi, Mikael Pittet, Camilla Engblom, Christina Pfirschke, Xavier Préville, Gilles Uzè, Robert D Schreiber, Melvyn T Chow, Mark J Smyth, Enrico Proietti, Fabrice André, Guido Kroemer, Laurence Zitvogel
Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10)...
November 2014: Nature Medicine
Hélène Bugaut, Mélanie Bruchard, Hélène Berger, Valentin Derangère, Ludivine Odoul, Romain Euvrard, Sylvain Ladoire, Fanny Chalmin, Frédérique Végran, Cédric Rébé, Lionel Apetoh, François Ghiringhelli, Grégoire Mignot
Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP...
2013: PloS One
Sylvain Ladoire, Dalil Hannani, Marie Vetizou, Clara Locher, Laetitia Aymeric, Lionel Apetoh, Oliver Kepp, Guido Kroemer, François Ghiringhelli, Laurence Zitvogel
SIGNIFICANCE: Accumulating evidence indicates that the success of some anticancer treatments (select chemotherapies or radiotherapy or trastuzumab) could be related to the stimulation of an anticancer immune response through the induction of an immunogenic tumor cell death (ICD). RECENT ADVANCES: Preclinical data revealed that dying tumor cells can emit a series of danger signals (so-called "cell-death-associated molecular patterns" (CDAMP)) that will dictate the recruitment and activation of specific inflammatory phagocytes...
March 1, 2014: Antioxidants & Redox Signaling
Laura Senovilla, Ilio Vitale, Isabelle Martins, Maximilien Tailler, Claire Pailleret, Mickaël Michaud, Lorenzo Galluzzi, Sandy Adjemian, Oliver Kepp, Mireia Niso-Santano, Shensi Shen, Guillermo Mariño, Alfredo Criollo, Alice Boilève, Bastien Job, Sylvain Ladoire, François Ghiringhelli, Antonella Sistigu, Takahiro Yamazaki, Santiago Rello-Varona, Clara Locher, Vichnou Poirier-Colame, Monique Talbot, Alexander Valent, Francesco Berardinelli, Antonio Antoccia, Fabiola Ciccosanti, Gian Maria Fimia, Mauro Piacentini, Antonio Fueyo, Nicole L Messina, Ming Li, Christopher J Chan, Verena Sigl, Guillaume Pourcher, Christoph Ruckenstuhl, Didac Carmona-Gutierrez, Vladimir Lazar, Josef M Penninger, Frank Madeo, Carlos López-Otín, Mark J Smyth, Laurence Zitvogel, Maria Castedo, Guido Kroemer
Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin...
September 28, 2012: Science
Sylvain Ladoire, Kariman Chaba, Isabelle Martins, Abdul Qader Sukkurwala, Sandy Adjemian, Mickaël Michaud, Vichnou Poirier-Colame, Felipe Andreiuolo, Lorenzo Galluzzi, Eileen White, Mathias Rosenfeldt, Kevin M Ryan, Laurence Zitvogel, Guido Kroemer
Autophagy is an evolutionarily conserved catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Alterations in autophagic signaling are found in several human diseases including cancer. Here, we describe a validated immunohistochemical protocol for the detection of LC3 puncta in human formalin-fixed, paraffin-embedded cancer specimens that can also be applied to mouse tissues. In response to systemic chemotherapy, autophagy-competent mouse tumors exhibited LC3 puncta, which did not appear in mouse cancers that had been rendered autophagy-deficient by the knockdown of Atg5 or Atg7...
August 2012: Autophagy
S Ladoire, L Arnould, G Mignot, L Apetoh, C Rébé, F Martin, P Fumoleau, B Coudert, F Ghiringhelli
BACKGROUND: In HER2-overexpressing breast cancer, accumulating preclinical evidences suggest that some chemotherapies, like trastuzumab, but also taxanes, are able to trigger a T helper 1 (Th1) anticancer immune response that contribute to treatment success. T helper 1 immune response is characterised by the expression of the transcription factor T-bet in CD4 T lymphocytes. We hypothesised that the presence of such T cells in the tumour immune infiltrates following neoadjuvant chemotherapy would predict patient survival...
July 26, 2011: British Journal of Cancer
Sylvain Ladoire, François Martin, François Ghiringhelli
The accumulation of regulatory T cells (Tregs) at high density in various human carcinomas is generally associated with a poor prognosis, as expected from their capacity to inhibit antitumor immunity. Surprisingly, in patients bearing colorectal carcinoma (CRC), high regulatory T-cell infiltration is associated with a favorable prognosis, as shown by the analysis of seven clinical studies. To explain this paradox, we emphasize a putative role of the dense microbiological flora present in the large intestine with a trend toward translocation through the tumor...
July 2011: Cancer Immunology, Immunotherapy: CII
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