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The ability of conventional type-1 dendritic cells (cDC1) to cross-present tumor antigens to CD8+ T cells is critical for the induction of antitumor CTLs. Mice that are constitutively deficient in cDC1 cells have been reported to fail to respond to immunotherapy strategies based on checkpoint inhibitors. However, further work is needed to clarify the precise time during immunotherapy treatment that cDC1 cells are required for the beneficial effect of treatment. Here, we used a refined XCR1-DTR-Venus transgenic mouse model to acutely deplete cDC1 cells and trace their behavior using intravital microscopy. Diphtheria toxin–mediated cDC1 depletion prior to immunotherapy treatment with anti–PD-1 and/or anti-CD137 immunostimulatory mAbs completely ablated antitumor efficacy. The efficacy of adoptive T-cell therapy was also hampered by prior cDC1 depletion. After the onset of immunotherapy treatment, depletion of cDC1s only moderately reduced the therapeutic efficacy of anti–PD-1 and anti-CD137 mAbs. Intravital microscopy of liver-engrafted tumors revealed changes in the intratumoral behavior of cDC1 cells in mice receiving immunotherapy, and treatment with diphtheria toxin to deplete cDC1s impaired tumor T-cell infiltration and function. These results reveal that the functional integrity of the cDC1 compartment is required at the onset of various immunotherapies to successfully treat established tumors.Significance:These findings reveal the intratumoral behavior of cDC1 dendritic cells in transgenic mouse models and demonstrate that the efficacy of immunotherapy regimens is precluded by elimination of these cells.

PDF file - 1620K, Combo3 treatment induces infiltrates of blastic T lymphocytes and increases the CD8/Treg ratio.

4T1-derived spontaneous lung metastases

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Statistical comparisons for figures 1, 2, 4 and supplementary figure 1.

PDF file - 2166K, Granzyme B, perforin and FasL are upregulated on CD8+ T cells after Combo3 treatment.

Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3–dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+ T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8+ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo. These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. Cancer Res; 76(20); 5994–6005. ©2016 AACR.

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supplementary figure legends and supplementary material and methods section.

Mouse external beam irradiation setting and combinations of radiotherapy and anti-CD137 and/or anti-PD1 immunostimulatory monoclonal antibodies are safe and effective to treat MC38-derived bilateral tumors of which only one of the tumor sites is irradiated.

Ex-vivo irradiation of human carcinoma surgical expecimens gives rise to more intense expression of CD137 and PD-1 on infiltrating lymphocytes.

A course of radiotherapy plus immunostimulatory monoclonal antibodies anti-CD137 and anti-PD-1 mAb increases CD4 and CD8 T cells in the tumor infiltrate as well as the number of tumor antigen-specific CD8 T cells.

PDF file - 1818K, Activated T cells and tumor infiltrating lymphocytes express PD-1, B7-H1 (PD-L1), CD137 and OX40.

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PDF file - 4662K, Three week old mice present established multifocal hepatocellular carcinomas and neonatal mice express OVA mRNA in their livers.

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Supplementary Figures 1-5 from Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

Simple Summary The introduction of immunotherapy within the usual strategies for cancer treatment has meant an enormous advance in the survival of patients with very restrictive prognoses. However, a high percentage of patients still cannot benefit from it. The lack of response to immunotherapy is mainly due to resistance from the tumor stroma itself. The lymphatic endothelium constitutes a permeable vascular system from the stroma specially dedicated to balancing tissue homeostasis and leukocyte emigration. Most solid carcinomas present lymphatic microvasculature that participates in tumor progression ambivalently. On one hand, it facilitates the transit of immune cells toward the lymph nodes and therefore promotes the antitumor response; on the other hand, they constitute an accessible route through which tumor cells metastasize to the lymph nodes. Due to this double function, it is not easy to establish strategies that educate the lymphatic endothelium only in its antitumor function without compromising its participation in the immune response. In this review, we study how combinations of radiotherapy and immunotherapy can modulate lymphatic function to use them in therapeutic approaches. The study of lymphatic tumor vasculature has been gaining interest in the context of cancer immunotherapy. These vessels constitute conduits for immune cells' transit toward the lymph nodes, and they endow tumors with routes to metastasize to the lymph nodes and, from them, toward distant sites. In addition, this vasculature participates in the modulation of the immune response directly through the interaction with tumor-infiltrating leukocytes and indirectly through the secretion of cytokines and chemokines that attract leukocytes and tumor cells. Radiotherapy constitutes the therapeutic option for more than 50% of solid tumors. Besides impacting transformed cells, RT affects stromal cells such as endothelial and immune cells. Mature lymphatic endothelial cells are resistant to RT, but we do not know to what extent RT may affect tumor-aberrant lymphatics. RT compromises lymphatic integrity and functionality, and it is a risk factor to the onset of lymphedema, a condition characterized by deficient lymphatic drainage and compromised tissue homeostasis. This review aims to provide evidence of RT's effects on tumor vessels, particularly on lymphatic endothelial cell physiology and immune properties. We will also explore the therapeutic options available so far to modulate signaling through lymphatic endothelial cell receptors and their repercussions on tumor immune cells in the context of cancer. There is a need for careful consideration of the RT dosage to come to terms with the participation of the lymphatic vasculature in anti-tumor response. Here, we provide new approaches to enhance the contribution of the lymphatic endothelium to radioimmuno-oncology.

The study of lymphatic tumor vasculature has been gaining interest in the context of cancer immunotherapy. These vessels constitute conduits for immune cells’ transit toward the lymph nodes, and they endow tumors with routes to metastasize to the lymph nodes and, from them, toward distant sites. In addition, this vasculature participates in the modulation of the immune response directly through the interaction with tumor-infiltrating leukocytes and indirectly through the secretion of cytokines and chemokines that attract leukocytes and tumor cells. Radiotherapy constitutes the therapeutic option for more than 50% of solid tumors. Besides impacting transformed cells, RT affects stromal cells such as endothelial and immune cells. Mature lymphatic endothelial cells are resistant to RT, but we do not know to what extent RT may affect tumor-aberrant lymphatics. RT compromises lymphatic integrity and functionality, and it is a risk factor to the onset of lymphedema, a condition characterized by deficient lymphatic drainage and compromised tissue homeostasis. This review aims to provide evidence of RT’s effects on tumor vessels, particularly on lymphatic endothelial cell physiology and immune properties. We will also explore the therapeutic options available so far to modulate signaling through lymphatic endothelial cell receptors and their repercussions on tumor immune cells in the context of cancer. There is a need for careful consideration of the RT dosage to come to terms with the participation of the lymphatic vasculature in anti-tumor response. Here, we provide new approaches to enhance the contribution of the lymphatic endothelium to radioimmuno-oncology.

Cette communication s'est tenue lors de la soirée de restitution du plan d'observation de la pratique sportive à Brest (piloté par Thierry Michot -LABERS UR 3149-, en étroite collaboration avec la Direction des Sports et du Nautisme - commanditaire).

In this chapter, Nadine Bret-Rouzaut analyzes the technical and economic aspects of hydrocarbon exploration and production. The chapter begins with a presentation of the different actors in order to understand their respective roles. Then a focus is made on the different phases of an exploration-production project in order to highlight the cost structure and the nature of the risks related to each phase. Finally, an analysis of rent sharing according to the different taxation systems points out the profitability problems of this capital-intensive industry, which is facing many challenges related to climate change.

A loess-paleosol sequence in the Pampean Plain, central Argentina was analyzed geochemically, in order to evaluate the weathering signature and sedimentary recycling as well as to analyze the origin of these loessic sediments. Corralito I sequence is composed of three paleosols and a buried soil separated by loess layers. The loess-paleosol sequence shows a similar geochemical composition throughout, suggesting that pedogenesis has not been intense enough to mask the chemical signature of the parent material. Weathering indices (CIA, CIW, PIA and LWI), elemental ratios (Rb/Sr, CaO/TiO2 and Na2O/TiO2), and the A-CN-K ternary diagram indicate incipient chemical alteration for this sequence, compatible with a weathering-limited regime. As expected, paleosols (CIAs ~60)exhibit a slightly higher chemical alteration than loess layers (CIAs ~58). Mass balance calculations reveal the losses of some major oxides (i.e., CaO, Na2O)and Sr in the buried soil and paleosols compared to its loess mantles, reflecting the weathering of plagioclase. Besides, the losses of K2O and Ba in the buried soil and paleosols I and II, when compared to its loess layers, suggest the chemical alteration of K-feldspar. The chemical alteration of volcanic glass is evidenced by the relative losses of As in almost all levels. Conversely, the relative gains of Fe2O3 and MgO reveal that pyroxenes and amphiboles or Fe oxy-hydroxides are concentrated in paleosols and the buried soil compared to its loess mantles. The geochemical approach used to constrain the origin of these Pampean Plain loessic sediments indicates they derive mainly from the Andean region. Conversely, the Pampean ranges, the Paraná River basin and Uruguayan Precambrian outcrops, which were pointed out as minor local sources, do not contribute significantly to the loess deposits. This work also shows that Corralito I loess-paleosol sequence and other loess samples from Argentina do not evidence sedimentary recycling, suggesting that these Pampean Plain loess deposits are mainly composed by young materials derived from undifferentiated volcanic rocks. Fil: Campodonico, Verena Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; Argentina Fil: Rouzaut, Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; Argentina Fil: Pasquini, Andrea Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; Argentina

Pourquoi, en 2020, est-il toujours question d’un « ministère de l’Éducation nationale et de la Jeunesse » ? En effet, s’il existe un « ministère en charge des Sports », n’y aurait-il donc qu’une seule et même jeunesse pour laquelle un unique prisme d’analyse suffirait ? Sa définition semble évidente, voire acquise dans les mémoires collectives, mais Sylvain Bordiec, maître de conférences à l’Université de Bordeaux et spécialiste des exclusions sociales, rappelle à travers cet ouvrage la néces...

Breast cancer is one of the most common and malignant cancers nowadays. Like many cancers, it is extensively regulated by pro-angiogenic and pro-lymphangiogenic factors, which induce rapid vasculature growth. This results in aberrant vessels which enhance a pro-tumor environment by preventing treatment against cancer to get to the tumor, inducing the malignancy of cancer cells, and inhibiting the immune response. In the last years, antiangiogenic treatment was suggested as a possible way to eliminate the tumor-supporting environment. This approach was soon replaced by the judicious use of these anti-angiogenic molecules in normalizing concentrations, to prevent pro-tumor effects, such as cell malignification. In a novel approach to prevent these processes to occur, we have designed a treatment based on the normalization of the tumoral vasculature of triple-negative breast carcinoma, so they return to their physiological state. For this aim, we have analyzed the effects of the blockage of VEGF-A and VEGF-C signaling pathways (angiogenesis and lymphangiogenesis), by targeting their receptors, VEGFR2 and VEGFR3, with inhibitor molecules (DC101 antibody and SAR131675 molecules).

In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca+2 chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.

A Late Pleistocene–Holocene loess–paleosol sequence in central Argentina was studied to obtain a weathering insight and to probe geochemical tools as paleoclimatic proxies. Three paleosols and a buried soil interlayered with loess mantles compose Corralito I sequence (32°00′7″ S, 64°11′08″ W, 469 m a.s.l). Several weathering indices (CIA, CIA-K, and LWI) and elemental ratios (∑Bases/Al2O3, Rb/Sr, CaO/TiO2, Na2O/TiO2) were calculated. An incipient weathering degree throughout the sequence was detected, denoting that the parent material (i.e., loess mantles) has not been substantially modified by pedogenesis. Although a statistically significant correlation between magnetic susceptibility and several weathering indices was identified, the weathering intensity was not strong enough to produce a decrease in the magnetic signal of the paleosols, which is, in part, inherited from the detrital fraction. Paleoprecipitation indices, calculated using geochemical data, suggest slightly wetter conditions during paleosol formation when compared to loess. Paleosols were formed during humid conditions (paleosols II and II during MIS 5e, and paleosol I during MIS 3) with sedimentation pause and soil development, whereas loess layers were deposited during more arid conditions.