Induction de la mort cellaire dépendante de la caspase-1 dans le cancer du côlon

Le cancer du côlon reste un problème majeur de santé publique puisqu il constitue en France en 2013 le deuxième cancer en termes de mortalité. Les traitements de chimiothérapies classiques secondés par les thérapeutiques ciblées ne constituent pas toujours un arsenal efficace mettant ainsi en évidence la nécessité de trouver de nouvelles cibles thérapeutiques. Dans ce contexte, nous avons étudié le rôle de l activation de la caspase-1 sur la mort cellulaire de différentes lignées coliques humaines (HCT116, HT29, HCT8, SW480). Nous avons d abord démontré que les agonistes du récepteur Liver X Receptor (LXR), un récepteur nucléaire aux oxysterols, pouvaient activer une mort de type pyroptotique des cellules cancéreuses coliques sous l action de la construction d un inflammasomme et du clivage de la caspase-1. De plus, les agonistes LXR peuvent apparaître comme une thérapeutique ciblée puisque nous avons mis en évidence une perte de localisation nucléaire du récepteur LXR dans les cellules des tissus tumoraux coliques comparés à la muqueuse saine. Nous avons également démontré que l activation de la caspase-1 pouvait aussi avoir des effets délétères. Ainsi, dans une modélisation in vitro de chimiothérapie intrapéritonéale (CHIP), le traitement par oxaliplatine à forte dose à 42C pendant trente minutes provoque le clivage de la caspase-1 et la sécrétion de cytokines pro-inflammatoires qui pourraient expliquer les symptômes cliniques fébriles en l absence de bactériémie chez les patients ayant subi un tel protocole de CHIP. L activation de la caspase-1, dans un contexte tumoral, peut donc apparaître bénéfique lorsqu elle induit une mort de type pyroptotique des cellules cancéreuses coliques. Les cytokines pro-inflammatoires que la caspase-1 fait maturées et sécrétées doivent être contrôlées pour que son activation par les chimiothérapies conventionnelles ou par de nouvelles classes thérapeutiques soit utilisable en clinique.DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Evaluation of tumor immune contexture among intrinsic molecular subtypes helps to predict outcome in early breast cancer

Background The prognosis of early breast cancer is linked to clinic-pathological stage and the molecular characteristics of intrinsic tumor cells. In some patients, the amount and quality of tumor-infiltrating immune cells appear to affect long term outcome. We aimed to propose a new tool to estimate immune infiltrate, and link these factors to patient prognosis according to breast cancer molecular subtypes.Methods We performed in silico analyses in more than 2800 early breast cancer transcriptomes with corresponding clinical annotations. We first developed a new gene expression deconvolution algorithm that accurately estimates the quantity of immune cell populations (tumor immune contexture, TIC) in tumors. Then, we studied associations between these immune profiles and relapse-free and overall survival among the different intrinsic molecular subtypes of breast cancer defined by PAM50 classification.Results TIC estimates the abundance of 15 immune cell subsets. Both myeloid and lymphoid subpopulations show different spread among intrinsic molecular breast cancer subtypes. A high abundance of myeloid cells was associated with poor outcome, while lymphoid cells were associated with favorable prognosis. Unsupervised clustering describing the 15 immune cell subsets revealed four subgroups of breast tumors associated with distinct patient survival, but independent from PAM50. Adding this information to clinical stage and PAM50 strongly improves the prediction of relapse or death.Conclusions Our findings make it possible to refine the survival stratification of early patients with breast cancer by incorporating TIC in addition to PAM50 and clinical tumor burden in a prognostic model validated in training and validation cohorts

RAS status and neoadjuvant chemotherapy impact CD8+ cells and tumor HLA class I expression in liver metastatic colorectal cancer

Abstract Background T lymphocytes and HLA expression on tumor cell both influence prognostic of localized colorectal cancer, but their role following chemotherapy in patients with liver metastatic colorectal cancer (mCRC) was not addressed. Methods One hundred fourteen patients treated in curative intend of liver mCRC were included in this retrospective study. Patients were either untreated or treated with neoadjuvant therapy containing an anti-EGFR, bevacizumab or oxaliplatin. Immune densities were quantified in the tumor core and in invasive margin of metastases, using Qupath software or a pathologist’s quantification. CD8, NKp46, Foxp3, CD163, HLA, PD-L1 were analyzed and were correlated with progression free survival (PFS) and overall survival (OS) using multivariable Cox proportional hazards models. Results In the whole cohort only a high CD8+ cells infiltrate, a high HLA-I expression and wild-type RAS/RAF status were associated with a better overall survival in both univariate and multivariate model. Moreover, CD8+ cells immune infiltrate at invasive margin combined to HLA expression in cancer cell could increase patient’s outcome prediction. RAS status but not immune cell infiltrate was associated with HLA expression on tumor cells. In comparison to untreated patients, neoadjuvant chemotherapy induced CD8+ cells recruitment and increased PD-L1 staining in immune infiltrates only for WT RAS patients. In this context, anti-EGFR and oxaliplatin based chemotherapy are the most powerful to induce CD8+ cells mobilization within the metastatic site. Conclusions While CD8 infiltrate and HLA expression appear to be prognostic for mCRC, CD8 and PD-L1 infiltrate are enhanced by neoadjuvant chemotherapy in mCRC under RAS status dependence

Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination

International audienc

Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX-Bevacizumab Drug Treatment Regimen

International audienceHost 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 immuno-monitoring 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. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOL-FOX-bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX-bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. (C) 2016 AACR

Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy

International audienceBackgroundNo study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non–small-cell lung cancer (NSCLC).MethodsWe analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types.ResultsIn prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures.ConclusionCD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles