François Ghiringhelli

Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice

The release of adenosine triphosphate through autophagy can promote antitumor immune responses. Antineoplastic chemotherapies are particularly efficient when they elicit immunogenic cell death, thus provoking an anticancer immune response. Here we demonstrate that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent, but not autophagy-deficient, cancers attracted dendritic cells and T lymphocytes into the tumor bed. Suppression of autophagy inhibited the release of adenosine triphosphate (ATP) from dying tumor cells. Conversely, inhibition of extracellular ATP-degrading enzymes increased pericellular ATP in autophagy-deficient tumors, reestablished the recruitment of immune cells, and restored chemotherapeutic responses but only in immunocompetent hosts. Thus, autophagy is essential for the immunogenic release of ATP from dying cells, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when autophagy is disabled.

Consensus guidelines for the detection of immunogenic cell death

Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named “immunogenic cell death” (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.

STAT3 activation: A key factor in tumor immunoescape

Cancer growth is controlled by cancer cells (cell intrinsic phenomenon), but also by the immune cells in the tumor microenvironment (cell extrinsic phenomenon). Thus cancer progression is mediated by the activation of transcription programs responsible for cancer cell proliferation, but also induced proliferation/activation of immunosuppressive cells such as Th17, Treg or myeloid derived suppressor cells (MDSCs). One of the key transcription factors involved in these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on STAT3 activation in immune cells, and how it impacts on tumor progression.

Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress.

Dietary conjugated linoleic acids (CLA) are fatty acid isomers with anticancer activities produced naturally in ruminants or from vegetable oil processing. The anticancer effects of CLA differ upon the cancer origin and the CLA isomers. In this study, we carried out to precise the effects of CLA isomers, c9,t11 and t10,c12 CLA, on mechanisms of cell death induction in colon cancer cells. We first showed that only t10,c12 CLA treatment (25 and 50μM) for 72h triggered apoptosis in colon cancer cells without affecting viability of normal-derived colon epithelial cells. Exposure of colon cancer cells to t10,c12 CLA activated ER stress characterized by induction of eIF2α phoshorylation, splicing of Xbp1 mRNA and CHOP expression. Furthermore, we evidenced that inhibition of CHOP expression and JNK signaling decreased t10,c12 CLA-mediated cancer cell death. Finally, we showed that CHOP induction by t10,c12 CLA was dependent on ROS production and that the anti-oxidant N-acetyl-cysteine reduced CHOP induction-dependent cell death. These results highlight that t10,c12 CLA exerts its cytotoxic effect through ROS generation and a subsequent ER stress-dependent apoptosis in colon cancer cells.

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

PURPOSEnPatients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.nnnMETHODSnWe performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab.nnnRESULTSnCombination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.nnnCONCLUSIONnOur findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.

Immune effects of 5-fluorouracil: Ambivalence matters

Cytotoxic anticancer drugs can promote antitumor immune responses. The anticancer activity of 5-fluorouracil (5FU) relies on the restoration of T-cell immunity following the elimination of myeloid-derived suppressor cells (MDSCs). We have recently discovered that the 5FU-driven activation of the NLRP3 inflammasome in MDSCs promotes tumor angiogenesis by eliciting TH17 responses that compromise anticancer immunity. This underscores the need to combine 5-FU with NLRP3 inhibitors to prevent tumor progression.

Sodium citrate versus saline catheter locks for non-tunneled hemodialysis central venous catheters in critically ill adults: a randomized controlled trial

PurposeSodium citrate has antibacterial and anticoagulant properties that are confined to the catheter when used as a catheter lock. Studies of its use as a catheter lock in chronic hemodialysis patients suggest it may be efficacious in preventing infection and thrombotic complications. We compared sodium citrate with saline catheter locks for non-tunneled hemodialysis central venous catheters in critically ill adult patients. Primary endpoint was catheter life span without complication.MethodsThis was a randomized, controlled, open-label trial involving intensive care patients with acute renal failure requiring hemodialysis. Events were defined as catheter-related bloodstream infection and catheter malfunction.ResultsSeventy-eight patients were included. Median catheter life span without complication was 6xa0days (saline group) versus 12xa0days (citrate group) [hazard ratio (HR) 2.12 (95% CI 1.32–3.4), pxa0=xa00.0019]. There was a significantly higher rate of catheter malfunction in the saline group compared with in the citrate group (127 catheter events/1,000xa0catheter-days, saline group vs. 26 events/1,000xa0catheter-days, citrate group, pxa0<xa00.00001). There was no significant difference in incidence of infections between groups. We observed a significantly longer time to occurrence of infection in the citrate group (20xa0days vs. 14xa0days, HR 2.8, 95% CI 1.04–7.6, pxa0=xa00.04). By multivariate analysis, age and citrate group were the only independent factors that influenced catheter life span.ConclusionsThis study shows for the first time that citrate lock reduced catheter complications and increased catheter life span as compared to saline lock in critically ill adults requiring hemodialysis.

The interplay between the immune system and chemotherapy: emerging methods for optimizing therapy

Preclinical studies have revealed an unexpected ability of the immune system to contribute to the success of chemotherapy and radiotherapy. Anticancer therapies can trigger immune system activation by promoting the release of danger signals from dying tumor cells and/or the elimination of immunosuppressive cells. We have, however, recently discovered that some chemotherapies, such as 5-fluorouracil and gemcitabine, exert conflicting effects on anticancer immune responses. Although 5-fluorouracil and Gem selectively eliminated myeloid-derived suppressive cells in tumor-bearing rodents, these chemotherapies promoted the release of IL-1β and the development of pro-angiogenic IL-17-producing CD4 T cells. The ambivalent effects of chemotherapy on immune responses should thus be carefully considered to design effective combination therapies based on chemotherapy and immune modulators. Herein, we discuss how the initial findings underscoring the key role of the immune system in mediating the antitumor efficacy of anticancer agents could begin to translate into effective therapies in humans.

Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator

SummaryPlatinum(II) metallointercalators represent a new class of DNA-damaging antitumor complexes active in cisplatin- and oxaliplatin-resistant cell lines. In the first part of our work, we have screened in vitro a serie of 18 metallointercalators with the structure [Pt(AL)(IL)]2+ where ALu2009=u2009ethylenediamine (EN) or diaminocyclohexane in R,R- (RR) or S,S- (SS) configuration ; and IL = 1,10-phenanthroline with different degree of methylation : no methylation (PHEN), mono-methylated in position 4 (4ME) or 5 (5ME), or di-methylated in positions 4 and 7 (47ME) or in positions 5 and 6 (56ME) or tetramethylated in positions 3,4,7 and 8 (3478ME). Eight compounds: PHENEN, 56MEEN, 47MERR, 56MERR, 4MESS, 5MESS, 47MESS and 56MESS exhibited significant cytotoxic effect, equivalent or higher than cisplatin, oxaliplatin or carboplatin in the human HCT8 colon and IGROV1 ovarian cancer cell lines for both 1 and 24xa0h incubation time. The high cytotoxicity of the most active compound, the 56MESS, could be related to the hydrophobicity of the phenanthroline ligand that increases cellular uptake in human HCT8, HT29 (colon) and IGROV1 (ovarian) as well as in rat PROb colon cell lines. Unfortunately, intravenous or intraperitoneal administration of 56MESS had no antitumoral activity in BD-IX rats with peritoneal carcinomatosis induced by an intraperitoneal PROb cells inoculation. Moreover, 56MESS displayed nephrotoxicity at pharmacological dose. Thus, these data query the in vivo/in vitro correlation and reconsider the place of the in vivo screening to select adequate candidate drug for further preclinical and clinical developments.

Epidemiology and prognosis of synchronous and metachronous colon cancer metastases: A French population-based study

BACKGROUNDnEpidemiological data on synchronous and metachronous metastatic colon cancer are scarce. We assessed epidemiological characteristics and survival in synchronous and metachronous metastatic colon cancer in a French population.nnnMETHODSnOur study included 932 cases of metastatic colon cancer diagnosed in 1999-2010 and registered in a population-based cancer registry; 758 were synchronous colon metastases and 174 metachronous metastases from resected primary colon cancers diagnosed in 1999-2005. Univariate relative survival was calculated and a multivariate model with proportional hazard applied to net survival by interval was used.nnnRESULTSnMean age at diagnosis was 71.1 years for patients with metachronous metastasis and 71.4 years for those with synchronous metastasis (p=0.818). Patients with metachronous metastasis were more likely to have R0 resection (Odds Ratio: 3.05 [1.96-4.76], p<0.001) than patients with synchronous metastasis. Five-year relative survival was 7.2% for synchronous metastasis and 17.6% for metachronous metastasis (p<0.001), but did not differ significantly for patients with R0 resection (47.3% and 61.5% respectively, p=0.120). For patients not receiving chemotherapy risk of death was significantly lower in the metachronous metastasis group (Hazard Ratio=0.44 [0.32-0.60], p<0.001).nnnCONCLUSIONSnOn a population basis, synchronous metastasis is an independent poor prognostic factor in colon cancer. Chemotherapy and resection of all metastatic sites significantly improved the outcome in patients with synchronous metastasis.