Treg depletion followed by intracerebral CpG-ODN injection induce brain tumor rejection

Using brain lymphoma model, we demonstrate that immunotherapy combining Treg depletion (using anti-CD25 mAb PC61) followed by intracranial CpG-ODN administration induced tumor rejection in all treated mice and led to the establishment of a memory antitumor immune response in 60% of them. This protective effect was associated with a recruitment of NK cells and, to a lesser extent, of dendritic cells, B cells and T lymphocytes. NK cell depletion abolished the protective effect of the treatment, confirming a major role of NK cells in brain tumor elimination. Each treatment used alone failed to protect brain tumor bearing mice, revealing the therapeutic benefit of combining Treg depletion and local CpG-ODN injection

Th17 Cells Are Involved in the Local Control of Tumor Progression in Primary Intraocular Lymphoma

BACKGROUND: Th17 cells play an important role in the pathogenesis of many autoimmune diseases, but despite some reports of their antitumor properties, too little is known about their presence and role in cancers. Specifically, knowledge is sparse about the relation of Th17 to lymphoma microenvironments and, more particularly, to the microenvironment of primary intraocular B-cell lymphoma (PIOL), an aggressive lymphoma with a poor prognosis. METHODS AND PRINCIPAL FINDINGS: In this work, we investigated the presence of Th17 cells and their related cytokines in a syngeneic model of PIOL, a subtype of non-Hodgkin lymphoma. The very small number of lymphocytes trafficking in normal eyes, which represent a low background as compared to tumor-bearing eyes, allows us to develop the present model to characterize the different lymphocyte subsets present when a tumor is developing. IL-21 mRNA was expressed concomitantly with IL-17 mRNA in tumor-bearing eyes and intracellular expression of IL-17A and IL-21 in infiltrating CD4(+) T lymphocytes. Interestingly, IL-17A production by T cells was negatively correlated with tumor burden. We also showed that IL-21 but not IL-17 inhibits tumor cell proliferation in vitro. CONCLUSIONS: These data demonstrate that IL-17A and IL-21-producing CD4(+) T cells, referred as Th17 cells, infiltrate this tumor locally and suggest that Th17-related cytokines may counteract tumor progression via IL-21 production. Thus, Th17 cells or their related cytokines could be considered to be a new therapeutic approach for non-Hodgkin B-cell lymphomas, particularly those with an ocular localization

Bioluminescence-Based Tumor Quantification Method for Monitoring Tumor Progression and Treatment Effects in Mouse Lymphoma Models

International audienceAlthough bioluminescence imaging (BLI) shows promise for monitoring tumor burden in animal models of cancer, these analyses remain mostly qualitative. Here we describe a method for bioluminescence imaging to obtain a semi-quantitative analysis of tumor burden and treatment response. This method is based on the calculation of a luminoscore, a value that allows comparisons of two animals from the same or different experiments. Current BLI instruments enable the calculation of this luminoscore, which relies mainly on the acquisition conditions (back and front acquisitions) and the drawing of the region of interest (manual markup around the mouse). Using two previously described mouse lymphoma models based on cell engraftment, we show that the luminoscore method can serve as a noninvasive way to verify successful tumor cell inoculation, monitor tumor burden, and evaluate the effects of in situ cancer treatment (CpG-DNA). Finally, we show that this method suits different experimental designs. We suggest that this method be used for early estimates of treatment response in preclinical small-animal studies

Mouse models of primary central nervous system lymphomas: tools for basing funding and therapeutic strategies

International audiencePrimary central nervous system lymphomas (PCNSL) include ocular and cerebral lymphomas and are rare aggressive malignancies with poor prognoses. Compared with other lymphomas, they are a challenge for clinicians and scientists, for diagnosis and therapeutic progress and their prognosis remains unsatisfactory, because of the lack of molecular and biological knowledge. Indeed, several limitations of human sample present a major obstacle to the identification of the particular microenvironment of the sanctuary sites where these tumor cells grow. In addition, the generally poor overall condition and performance status of patients with PCNSL limit their participation in prospective trials. Therefore, animal models of PCNSL are essential for tumor microenvironment characterization and for antitumor response studying. In this review, we have compiled the B-and T-cell PCNSL mouse models that are used to improve our understanding of the lymphoma microenvironment, tropism and migration and to investigate novel therapeutic strategies

Influence of Tumor Location on the Composition of Immune Infiltrate and Its Impact on Patient Survival. Lessons from DCBCL and Animal Models

International audienceDiffuse large B-cell lymphomas (DLBCLs) are heterogeneous diseases growing either in nodal or extranodal locations including the central nervous system. One key issue is to decipher the prognostic value of immune cells infiltrating these tumors as DLBCLs developing in sanctuaries are more aggressive than nodal DLCBLs. Here, we summarize available data from the literature regarding the prognostic values of the different immune cell types found in these two types of human primary tumors (i.e., nodal vs brain). In nodal DLBCLs, memory T-cells and dendritic cells (DCs) densities are of good prognostic value whereas the influence of regulatory T-cells (Tregs) is less clear, in accordance with other types of cancers. Data for primary central nervous system lymphomas are very sparse for these cell types. By contrast, CD8(+) cytotoxic T-cells seem to be of poor prognosis in either location. Their presence is linked to a loss of MHC expression providing a possible immune escape mechanism for these tumors. Clearly, tumor-associated macrophages are not associated to a significant prognostic value even in the brain where they highly infiltrate the tumor. Animal models indicate some specific features of lymphoma developing in sanctuaries by comparison to splenic location, with a higher infiltration of Tregs and less DCs, most likely reflecting the immunosuppressive context of these organs. All these informations illustrate the high impact of the immune system on patient outcome, encourage the pursuit of the immune environment's analysis and of immunotherapeutic approaches

Naturally occurring CD4+CD25+Foxp3+ regulatory T cells participate in but do not govern immune escape in primary intraocular lymphoma

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Surface atmosphere exchanges of chemical compounds in a wet savanna ecosystem site in West Africa during the DACCIWA field campaign

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Eosinophilic granulomatosis with polyangiitis in children: Data from the French RespiRare® cohort.

To describe the characteristics of pediatric cases of eosinophilic granulomatosis with polyangiitis (EGPA), a systemic necrotizing vasculitis rarely diagnosed in children, retrieved from the French Reference Center for rare pediatric lung diseases and compared with adult cases included in the French Vasculitis Study Group cohort. We collected information on pediatric EGPA disease presentation, management, and outcome. Cases met the Lanham criteria and/or American College of Rheumatology classification criteria. Fourteen cases of pediatric EGPA were included, from 1980 to 2012, with a median follow-up of 58.5 months. Median age at diagnosis was 12.3 years. All cases had respiratory involvement. The organ systems most frequently involved were the upper airway (85%), skin (71%), digestive tract (64%), and heart (57%). Neurological and renal involvement were rare. Four of the fourteen children were positive for ANCA (30.7%). During follow-up, three children required intensive care and one child died. The relapse rate was 64%. In comparison with an adult cohort, we found more ENT, heart, and digestive-tract involvement, and fewer neurological manifestations. In children, the delay between asthma onset and diagnosis was shorter, and biopsies showed fewer features of vasculitis. This French cohort is the biggest pediatric EGPA series described to date, with a long follow-up period. The findings confirm that pediatric EGPA has specific clinical, radiological, and histological characteristics that differ from adult EGPA. Development of systemic symptoms, and consequently diagnosis, occur with a shorter delay in children, mainly during the eosinophilic phase and leading to a specific presentation

Preclinical study of Ublituximab, a Glycoengineered anti-human CD20 antibody, in murine models of primary cerebral and intraocular B-cell lymphomas

International audiencePURPOSE: Primary cerebral lymphoma (PCL) and primary intraocular lymphoma (PIOL) belong to the systemic diffuse large B-cell lymphoma family and are characterized by the presence of CD20(+) lymphoma B cells in the brain or the eye. These highly aggressive malignancies have a poor prognosis and no specific therapy. The presence of effector immune cells in the damaged brain and vitreous suggests that treatment with anti-human CD20 (hCD20) monoclonal antibodies might be effective. We developed murine models of PCL and PIOL to assess the intracerebral and intraocular antitumor effect of ublituximab, a promising glycoengineered anti-hCD20 mAb with a high affinity for FcgammaRIIIa (CD16) receptors. METHODS: The murine lymphoma B-cell line A20.IIA-GFP-hCD20 (H-2(d)) was injected into the right cerebral striatum or the vitreous of immunocompetent adult BALB/c mice (H-2(d)). Four to 7 days later, ublituximab was injected intracerebrally or intravitreously into the tumor site. Rituximab was the reference compound. Survival was monitored for injected mice; histopathological and flow cytometric analyses were performed to study tumor growth and T-cell infiltration. RESULTS: Single doses of ublituximab, injected intracerebrally or intravitreously, had a marked antitumor effect, more pronounced than that obtained with the same dose of rituximab in these conditions. The reduction in tumor cells was correlated with an increased proportion of CD8(+) T cells. This efficacy was observed only against lymphoma B cells expressing hCD20. CONCLUSIONS: These in vivo results confirm the potential of the glycoengineered anti-hCD20 mAb ublituximab as an innovative therapeutic approach to treat primary central nervous system lymphoma and other B-cell lymphomas