Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma

Introduction The aim of this study was to investigate endogenous retrovirus (ERV) expression and type I interferon (IFN) activation in human pleural mesothelioma (PM) and their association with clinical outcome. Methods The expression of ERV was determined from PM cohorts and mesothelial precursor RNA sequencing data. The expression of ERV was confirmed by quantitative polymerase chain reaction (qPCR). Methylation of genomic DNA was assessed by quantitative methylation-specific PCR. DNA demethylation was induced in cells by demethylating agent 5-Aza-2’-deoxycytidine (5-Aza-CdR) treatment. To block type I IFN signaling, the cells were treated with ruxolitinib or MAVS silencing. The expression of IFN-stimulated genes (ISGs) was determined by qPCR and Western blot. Circulating ERVs were detected by qPCR. Results Long terminal repeats (LTRs) represent the most abundant transposable elements up-regulated in PM. Within the LTR, ERVmap_1248 and LTR7Y, which are specifically enriched in PM, were further analyzed. The 5-Aza-CdR treatment increased the levels of ERVmap_1248 expression and induced ERVmap_1248 promoter demethylation in mesothelial cells. In addition, ERVmap_1248 promoter was more demethylated in the mesothelioma tissue compared with nontumor tissue. The 5-Aza-CdR treatment of the mesothelial cells also increased the levels of ISGs. Basal ISG expression was higher in the mesothelioma cells compared with the mesothelial cells, and it was significantly decreased by ruxolitinib treatment or MAVS silencing. Furthermore, ISG expression was higher in the tumor tissue with high expression levels of ERVmap_1248. High expression of ERVmap_1248 was associated with longer overall survival and BAP1 mutations. ERVmap_1248 and LTR7Y can be detected in the PM plasma. Conclusions We provide clues for patient stratification especially for immunotherapy where best clinical responses are associated with an activated basal immune response

Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures

Recent Progresses of Oncolytic Immunotherapy

International audienceOncolytic immunotherapy, also known as anti-tumor virotherapy, is a therapeutic approach using oncolytic viruses that preferentially or exclusively infect and kill tumor cells. In this short review, we discuss recent advances of this therapeutic strategy

Oncolytic Viruses and Immune Checkpoint Inhibitors

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L'immuno-virothérapie oncolytique, une stratégie émergente de traitement du cancer

International audienceOncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvironment (for converting “cold” tumors into “hot” tumors), could quickly become a new valuable weapon in the oncologist’s therapeutic arsenal.L'immuno-virothérapie oncolytique consiste à utiliser des virus réplicatifs pour cibler les cellules tumorales, provoquer leur lyse sélective, et activer ainsi la réponse immunitaire anti-tumorale. Cette approche, dont le concept est relativement ancien, est devenue une réalité thérapeutique depuis 2015 avec la mise sur le marché d'un premier produit, le T-Vec, pour le traitement du mélanome métastatique. Dans cette revue, nous rappelons le principe de la thérapie oncolytique et ses effets positifs sur la réponse immunitaire anti-tumorale. Les mécanismes mis en jeu justifient notamment leur utilisation en combinaison des inhibiteurs de points de contrôle immunitaire. En parallèle des nombreuses avancées précliniques, le développement clinique est très actif. On dénombre une cinquantaine d'essais de phases I à III en cours dans une grande variété d'indications, de voies d'administration et de combinaison. Nous faisons le pari que cette classe émergente multifonctionnelle, qui permet de reprogrammer le microenvironnement tumoral (de convertir les tumeurs « froides » en tumeurs « chaudes ») pourrait devenir assez rapidement une nouvelle arme pré-cieuse dans l'arsenal thérapeutique de l'oncologue. Mots clés : immunothérapie, virus oncolytique, immunité anti-tumorale Oncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvi-ronment (for converting "cold" tumors into "hot" tumors), could quickly become a new valuable weapon in the oncologist's therapeutic arsenal

L'immuno-virothérapie oncolytique, une stratégie émergente de traitement du cancer

International audienceOncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvironment (for converting “cold” tumors into “hot” tumors), could quickly become a new valuable weapon in the oncologist’s therapeutic arsenal.L'immuno-virothérapie oncolytique consiste à utiliser des virus réplicatifs pour cibler les cellules tumorales, provoquer leur lyse sélective, et activer ainsi la réponse immunitaire anti-tumorale. Cette approche, dont le concept est relativement ancien, est devenue une réalité thérapeutique depuis 2015 avec la mise sur le marché d'un premier produit, le T-Vec, pour le traitement du mélanome métastatique. Dans cette revue, nous rappelons le principe de la thérapie oncolytique et ses effets positifs sur la réponse immunitaire anti-tumorale. Les mécanismes mis en jeu justifient notamment leur utilisation en combinaison des inhibiteurs de points de contrôle immunitaire. En parallèle des nombreuses avancées précliniques, le développement clinique est très actif. On dénombre une cinquantaine d'essais de phases I à III en cours dans une grande variété d'indications, de voies d'administration et de combinaison. Nous faisons le pari que cette classe émergente multifonctionnelle, qui permet de reprogrammer le microenvironnement tumoral (de convertir les tumeurs « froides » en tumeurs « chaudes ») pourrait devenir assez rapidement une nouvelle arme pré-cieuse dans l'arsenal thérapeutique de l'oncologue. Mots clés : immunothérapie, virus oncolytique, immunité anti-tumorale Oncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvi-ronment (for converting "cold" tumors into "hot" tumors), could quickly become a new valuable weapon in the oncologist's therapeutic arsenal

MUC1-Specific Cytotoxic T Lymphocytes in Cancer Therapy: Induction and Challenge

MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials

Viral cancer therapies : are they ready for combination with other immunotherapies ?

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Chômage et politique de l'emploi 1981-1983

[fre] Cet article tente d'expliquer pourquoi et comment la faible progression du chômage entre la mi-1982 et les derniers mois de 1983 a été possible. Pour ce faire nous examinons les divers dispositifs de lutte contre le chômage mis en place par les pouvoirs publics au cours des années 1981-1983, en proposant une évaluation de leur impact sur la variation du chômage. D'après nos estimations, l'ensemble des mesures ont permis de freiner la hausse annuelle moyenne des demandeurs d'emplois de 150 000 personnes en 1981, 260 000 personnes en 1982 et 275 000 personnes en 1983. La politique « active » de l'emploi — créations d'emplois publics, réduction de la durée du travail, aides aux créations d'emplois et politique macroéconomique — a représenté 50 % des chômeurs évités en 1981, 72 % en 1982 mais seulement 37 % en 1983. La politique de formation et les dispositifs de cessation anticipée d'activité — garanties de ressources, contrats de solidarité — ont permis de freiner la hausse du chômage d'environ 60 000 personnes par an en 1981-1982 et 125 000 en 1983, soit respectivement 44 %, 24 % et 46 % du total des chômeurs évités. Les opérations menées par l'ANPE sur les chômeurs de longue durée ont permis d'éviter 15 000 chômeurs en 1982 et 45 000 en 1983. Même si ces évaluations restent de simples ordres de grandeur, elles montrent que les dispositifs de lutte contre le chômage ont eu un impact important. Toutefois, ils ont maintenant atteint leur effet maximum et il est à craindre que les mois qui viennent soient nettement moins favorables sur le front du chômage, sauf si tout ou partie des mesures qui ont été prises au cours de la période étudiée sont reconduites et amplifiées, en particulier la réduction de la durée du travail (y compris le développement du temps choisi). [eng] This article attempts to explain why and how the low progression of unemployment between mid 1982 and the last months of 1983 was made possible. We shall therefore examine the different devices installed by the government from 1981 through 1983 to fight unemployment, and we shall propose an evaluation of their impact on unemployment changes. According to our estimates, the body of measures enables to slow down the average annual rise of registered work applicants by 150 000 persons in 1981, 260 000 in 1982 and 275 000 in 1983. The « active » employment policy — creation of public employments, reduction of the work period, aid to the creation of employments and macro-economic policy — represented 50 % of would be unemployed workers in 1981, 72 % in 1982 but only 37 % in 1983. The training policy and the devices of anticipated cessation of activity — income guarantees, solidarity contracts — enabled to slow down the rise of unemployment by about 60 000 persons a year in 1981-1982 and 125 000 in 1983, or respectively 44 %, 24 % and 46 % of the total would be unemployed workers. The operations lead by the National Employment Agency (ANPE) on long term unemployed workers enabled to avoid 15 000 unemployed workers in 1982 and 45 000 in 1983. Even if these evaluations remain simple orders of magnitude, they do show that the devises used to fight unemployment have had an important impact. Nonetheless, they have now attained their maximum effect, and it may be much less gratifying on the unemployment front, unless all or a part of the measures that were undertaken over the period studied here are renewed and amplified, in particular the reduction of the work period (including the development of flexible hours).