Search

Introduction: Nasopharyngeal carcinoma (NPC) is a major public health problem in several countries, especially those in Southeast Asia and North Africa. In its typical poorly differentiated form, the Epstein-Barr virus (EBV) genome is present in the nuclei of all malignant cells with restricted expression of a few viral genes. The malignant phenotype of NPC cells results from the influence of these viral products in combination with cellular genetic, epigenetic and functional alterations. With regard to host/tumor interactions, NPC is a remarkable example of immune escape in the context of a hot tumor.Areas covered: This article has an emphasis on emerging therapeutic targets that are considered upstream or at an early stage of clinical application. It examines targets related to cellular oncogenic alterations, latent EBV infection and tumor interactions with the immune system.Expert opinion: There is a remarkable emergence of new agents that target EBV products. The clinical application of these agents would benefit from a systematic and comprehensive molecular classification of NPCs and from easy access to pre-clinical models in public repositories. There is a strong rationale for more investigations on the potential of immune modulators, especially those related to NK cells.

International audience; Mechanisms of tumor immune escape are quite diverse and require specific approaches for their exploration in syngeneic tumor models. In several human malignancies, galectin-9 (gal-9) is suspected to contribute to the immune escape. However, in contrast with what has been done for the infiltrating cells, the contribution of gal-9 produced by malignant cells has never been demonstrated in an animal model. Therefore, we derived isogenic clones—either positive or negative for gal-9—from the MB49 murine bladder carcinoma cell line. A progressive and consistent reduction of tumor growth was observed when gal-9-KO cells were subjected to serial transplantations into syngeneic mice. In contrast, tumor growth was unaffected during parallel serial transplantations into nude mice, thus linking tumor inhibition to the enhancement of the immune response against gal-9-KO tumors. This stronger immune response was at least in part explained by changing patterns of response to interferon-γ. One consistent change was a more abundant production of CXCL10, a major inflammatory factor whose production is often induced by interferon-γ. Overall, these observations demonstrate for the first time that serial transplantation into syngeneic mice can be a valuable experimental approach for the exploration of novel mechanisms of tumor immune escape.; Les mécanismes d'échappement à l'immunité anti-tumorale sont assez divers et nécessitent des approches spécifiques pour être explorés de façon appropriée dans des modèles tumoraux syngéniques. Dans plusieurs affections malignies humaines, on suspecte la galectine-9 (gal-9) de contribuer à l'échappement immunitaire. Cependant, contrairement à ce qui a été fait pour les cellules infiltrantes, la contribution de la gal-9 produite par les cellules malignes n'a jamais été démontrée dans un modèle animal. Par conséquent, nous avons dérivé des clones isogéniques - positifs ou négatifs pour la gal-9 - à partir de la lignée cellulaire de carcinome vésical murin MB49. Une réduction progressive et reproductible de la croissance tumorale a été observée lorsque des cellules MB49 invalidées pour la gal-9 ont fait l'objet de transplantations en série dans des souris syngéniques. En revanche, la croissance tumorale n'a pas été affectée lors de transplantations en série réalisées de façon parallèle chez des souris nu/nu, démontrant ainsi le lien entre l'inhibition de la croissance tumorale et l'amélioration de la réponse immunitaire contre les tumeurs invalidées pour la gal-9. Cette réponse immunitaire plus forte s'expliquait au moins en partie par une modification des modalités de réponse à l'interféron-γ. Le changement le plus constamment observé était une production plus abondante de CXCL10, un facteur inflammatoire majeur dont la production est souvent induite par l'interféron-γ. Dans l'ensemble, ces observations démontrent pour la première fois que la transplantation tumorale itérative chez des souris syngéniques peut être une approche expérimentale précieuse pour l'exploration de nouveaux mécanismes d'échappement à l'immunité anti-tumorale.

Galectin-9 (Gal-9) is known to enhance the expansion of myeloid-derived suppressor cells (MDSCs) in murine models. Its contribution to the expansion of MDSCs in human malignancies remain to be investigated. We here report that Gal-9 expression in nasopharyngeal carcinoma (NPC) cells enhances the generation of MDSCs (CD33+CD11b+HLA-DR−) from CD33+ bystander cells. The underlying mechanisms involve both the intracellular and secreted Gal-9. Inside carcinoma cells, Gal-9 up-regulates the expression of a variety of pro-inflammatory cytokines which are critical for MDSC differentiation, including IL-1β and IL-6. This effect is mediated by accelerated STING protein degradation resulting from direct interaction of the Gal-9 carbohydrate recognition domain 1 with the STING C-terminus and subsequent enhancement of the E3 ubiquitin ligase TRIM29-mediated K48-linked ubiquitination of STING. Moreover, we showed that extracellular Gal-9 secreted by carcinoma cells can enter the myeloid cells and trigger the same signaling cascade. Consistently, high concentrations of tumor and plasma Gal-9 are associated with shortened survival of NPC patients. Our findings unearth that Gal-9 induces myeloid lineage-mediated immunosuppression in tumor microenvironments by suppressing STING signaling.

Cancer immunology immunotherapy : CII (2020). doi:10.1007/s00262-020-02681-x, Published by Springer, Heidelberg

Nasopharyngeal carcinoma (NPC) is an EBV-associated neoplasm occurring endemically in Southeast Asia and sporadically all over the world. In children and adolescents, high cure rates have been obtained using chemotherapy, radiochemotherapy and maintenance therapy with interferon beta (IFNβ). The mechanism by which IFNβ contributes to a low systemic relapse rate has not yet been fully revealed. NK cells and serum samples from two patients with NPC were analyzed before and at different time points during IFNβ therapy, for assessment of TRAIL expression and NK cell cytotoxicity. Cytotoxicity was measured using the calcein release assay and the contribution of different death effector pathways was analyzed using specific inhibitors. Treatment with IFNβ induced TRAIL expression on patients’ NK cells and increased their cytotoxicity against NPC targets in vitro. NK cell-mediated cytotoxicity was predominately mediated via TRAIL. IFNβ also induced the production of soluble TRAIL (sTRAIL) by NK cells and its release upon contact with NPC cells. IFNβ treatment increased serum levels of sTRAIL in patients. Moreover, sTRAIL concentrated from patients’ serum samples induced apoptosis ex vivo in NPC cells from a patient-derived xenograft. Increased cytotoxicity of NK cells against NPC cells and increased serum levels of biologically active TRAIL in patients treated with IFNβ could be a means to eliminate micrometastatic disease and explain the low systemic relapse rate in this patient group.

International audience; Extra-cellular galectin-9 (gal-9) is an immuno-modulatory protein with predominant immuno-suppressive effects. Inappropriate production of gal-9 has been reported in several human malignancies and viral diseases like nasopharyngeal, pancreatic and renal carcinomas, metastatic melanomas and chronic active viral hepatitis. Therefore therapeutic antibodies neutralizing extra-cellular gal-9 are expected to contribute to immune restoration in these pathological conditions. Two novel monoclonal antibodies targeting gal-9-Gal-Nab 1 and 2-have been produced and characterized in this study. We report a protective effect of Gal-Nab1 and Gal-Nab2 on the apoptotic cell death induced by gal-9 in primary T cells. In addition, they inhibit late phenotypic changes observed in peripheral T cells that survive gal-9-induced apoptosis. Gal-Nab1 and Gal-Nab2 bind nearly identical, overlapping linear epi-topes contained in the 213-224 amino-acid segments of gal-9. Nevertheless, they have some distinct functional characteristics suggesting that their three-dimensional epitopes are distinct. These differences are best demonstrated when gal-9 is applied on Jurkat cells where Gal-Nab1 is less efficient than Gal-Nab2 in the prevention of apoptotic cell death. In addition, Gal-Nab1 stimulates non-lethal phosphatidylserine translocation at the plasma membrane and calcium mobilization triggered by gal-9 in these cells. Both Gal-Nab1 and 2 cross-react with murine gal-9. They bind its natural as well as its recombinant form. This cross-species recognition will be an advantage for their assessment in pre-clinical tumor models.

The considerable progress achieved in the past 10 years in the field of tumor biology and therapeutics has strengthened the idea that cancer is not only a cellular but also a tissue disease. This concept is likely to apply to nasopharyngeal carcinoma (NPC), characterized by the consistent expression of oncogenic viral proteins in a context of inflammation and immune escape (1). In its typical undifferentiated form, NPC is constantly associated with the Epstein-Barr virus, whose genome is contained in the nuclei of all malignant cells, but not in the surrounding tissue. Latency is the predominant mode of virus-cell interactions, meaning that most viral genes are silent in the vast majority of malignant cells. However, a small fraction of them are consistently expressed coding a handful of viral products, both viral proteins and untranslated RNAs, most of them with proven oncogenic properties. The inflammatory context of NPC is obvious for pathologists: almost all NPC primary tumors are heavily infiltrated by non-malignant leucocytes, mainly T-lymphocytes but also B lymphocytes, macrophages, dendritic cells and neutrophils. This inflammatory infiltration often disappears in metastatic lesions. The immune escape is also obvious because of the rapid proliferation of malignant cells despite the consistent expression of EBNA1, LMP1 and LMP2 which are known to be the targets of CD4+ and CD8+ cytotoxic T-cells in EBV-carriers. One interpretation of the paradox of tumor inflammation combined with tumor immune escape is that malignant cells in the primary tumor benefit to some extent from the proximity of leucocytes while developing mechanisms of immune escape.