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Kepp O.,Metabolomics and Cell Biology Platforms | Kepp O.,French Institute of Health and Medical Research | Semeraro M.,French Institute of Health and Medical Research | Bravo-San Pedro J.M.,French Institute of Health and Medical Research | And 14 more authors.
Seminars in Cancer Biology | Year: 2015

Cancer cells exposed to some forms of chemotherapy and radiotherapy die while eliciting an adaptive immune response. Such a functionally peculiar variant of apoptosis has been dubbed immunogenic cell death (ICD). One of the central events in the course of ICD is the activation of an endoplasmic reticulum (ER) stress response. This is instrumental for cells undergoing ICD to emit all the signals that are required for their demise to be perceived as immunogenic by the host, and culminates with the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). In particular, eIF2α phosphorylation is required for the pre-apoptotic exposure of the ER chaperone calreticulin (CALR) on the cell surface, which is a central determinant of ICD. Importantly, phosphorylated eIF2α can be quantified in both preclinical and clinical samples by immunoblotting or immunohistochemistry using phosphoneoepitope-specific monoclonal antibodies. Of note, the phosphorylation of eIF2α and CALR exposure do not necessarily correlate with each other, and neither of these parameters is sufficient for cell death to be perceived as immunogenic. Nonetheless, accumulating data indicate that assessing the degree of phosphorylation of eIF2α provides a convenient parameter to monitor ICD. Here, we discuss the role of the ER stress response in ICD and the potential value of eIF2α phosphorylation as a biomarker for this clinically relevant variant of apoptosis. © 2015 Elsevier Ltd.


Pedro J.M.B.-S.,French Institute of Health and Medical Research | Pedro J.M.B.-S.,University of Paris Descartes | Wei Y.,Metabolomics and Cell Biology Platforms | Sica V.,French Institute of Health and Medical Research | And 7 more authors.
Autophagy | Year: 2015

Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT- 737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members. © 2015, Jose Manuel Bravo-San Pedro, Yongjie Wei, Valentina Sica, Maria Chiara Maiuri, Zhongju Zou, Guido Kroemer, and Beth Levine.


Ladoire S.,Georges Francois Leclerc Center | Ladoire S.,French Institute of Health and Medical Research | Penault-Llorca F.,Center Jean Perrin | Penault-Llorca F.,University of Auvergne | And 19 more authors.
Autophagy | Year: 2015

In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B+ puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B+ puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B+ puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B+ puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B+ puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26–0.89]; P D 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05–0.85]; P D 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1+ LC3B+ double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B+ puncta and nuclear HMGB1 is a positive predictor for longer BC survival. © 2015 Taylor and Francis Group, LLC.


Ladoire S.,Georges Francois Leclerc Center | Ladoire S.,University of Burgundy | Ladoire S.,French Institute of Health and Medical Research | Enot D.,Metabolomics and Cell Biology Platforms | And 7 more authors.
OncoImmunology | Year: 2016

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. © 2016 Taylor & Francis Group, LLC.


Stoll G.,University of Paris Descartes | Stoll G.,French Institute of Health and Medical Research | Stoll G.,University Pierre and Marie Curie | Zitvogel L.,Metabolomics and Cell Biology Platforms | And 6 more authors.
OncoImmunology | Year: 2016

Recently, we interrogated public microarray databases with regard to the expression patterns of metagenes corresponding to major immune cell subtypes present in malignant tumors. This analysis, which involved approximately 3,500 tumor samples, revealed organ-specific differences in the composition of the immune infiltrate as well as in the correlation among distinct cell-type specific metagenes, reflecting changes in the functional organization of the anticancer immune response. © 2016 Taylor & Francis Group, LLC.


Stoll G.,University of Paris Descartes | Stoll G.,French Institute of Health and Medical Research | Stoll G.,University Pierre and Marie Curie | Bindea G.,University of Paris Descartes | And 15 more authors.
Oncotarget | Year: 2015

Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers.


Ladoire S.,Georges Francois Leclerc CenterDijon | Ladoire S.,University of Burgundy | Ladoire S.,French Institute of Health and Medical Research | Enot D.,Metabolomics and Cell Biology Platforms | And 27 more authors.
Autophagy | Year: 2016

ABSTRACT: 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. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8+ cells and more FOXP3+ or CD68+ cells, resulting in a major drop in the CD8+:FOXP3+ or CD8+:CD68+ ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3+ and CD68+ cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance. © 2016 Taylor & Francis.


Stoll G.,University of Paris Descartes | Stoll G.,French Institute of Health and Medical Research | Enot D.,Metabolomics and Cell Biology Platforms | Mlecnik B.,University of Paris Descartes | And 11 more authors.
OncoImmunology | Year: 2014

There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Based on these premises, we attempted to identify metagenes that reflect an intratumoral immune response or local stress responses in the transcriptomes of breast cancer patients. No consistent correlations between immune- and stress-related metagenes could be identified across several cohorts of patients, representing a total of 1045 mammary carcinomas. Moreover, few if any, of the stress-relevant metagenes influenced the probability of pathological complete response to chemotherapy. In contrast, several immune-relevant metagenes had a significant positive impact on response rates. This applies in particular to a CXCL 13-centered, highly reproducible metagene signature reflecting the intratumoral presence of interferon-γ-producing T cells. © 2014 Landes Bioscience.


PubMed | Gustave Roussy Cancer Campus, Institute of Hematology and Blood Transfusion, Sotio, Metabolomics and Cell Biology Platforms and 4 more.
Type: | Journal: Blood | Year: 2016

Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called damage-associated molecular patterns, DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death (ICD) to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from acute myeloid leukemia (AML) patients exposed multiple DAMPs including calreticulin (CRT), heat-shock protein 70 (HSP70) and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed (ecto-)CRT correlated with an increased proportion of natural killer (NK) cells and effector memory CD4

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