Hypovitaminosis D is associated with depression and anxiety in schizophrenia: results from the national FACE-SZ cohort. Running title: hypovitaminosis D, depression and anxiety in schizophrenia

International audienceBackground. Guidelines have been edited for the treatment of schizophrenia (SZ) and bipola

Cellular Composition and Contribution of Tertiary Lymphoid Structures to Tumor Immune Infiltration and Modulation by Radiation Therapy

Immune-based anti-cancer strategies combined with radiation therapy (RT) are actively being investigated but many questions remain, such as the ideal treatment scheme and whether a potent immune response can be generated both locally and systemically. In this context, tumor-associated tertiary lymphoid structures (TLS) have become a subject of research. While TLS are present in several types of cancer with strong similarities, they are especially relevant in medullary breast carcinoma (MBC). This suggests that MBC patients are ideally suited for investigating this question and may benefit from adapted therapeutic options. As RT is a corner-stone of MBC treatment, investigating interactions between RT and TLS composition is also clinically relevant. We thus first characterized the lymphoid structures associated with MBC in a patient case report and demonstrated that they closely resemble the TLS observed in a genetical mouse model. In this model, we quantitatively and qualitatively investigated the cellular composition of the tumor-associated TLS. Finally, we investigated TLS regulation after hypo-fractionated RT and showed that RT induced their acute and transient depletion, followed by a restoration phase. This study is the first work to bring a comprehensive and timely characterization of tumor-associated TLS in basal conditions and after RT. It highlights cellular targets (i.e., Tregs) that could be selectively modulated in subsequent studies to optimize anti-tumor immune response. The study of TLS modulation is worth further investigation in the context of RT and personalized medicine

Tumor associated regulatory CD4+ T cell in breast cancer, recruitment, and role of ICOS/ICOS-L interaction in their activation by altered plasmacytoïde dendritic cells

Le cancer du sein représente un problème de santé publique. Les efforts déployés pour définir de nouvelles stratégies thérapeutiques ont mis en lumière les mécanismes développés par la tumeur pour inhiber l'instauration d'une réponse immune adaptative efficace. La tumeur favorise la mise en place d'une immunosubversion, caractériisée par la fort infiltration d'une sous-population de lymphocytes T CD4 régulateurs (Treg). Les Treg jouent un rôle central dans les mécanismes de contrôle de réactions pro-inflammatoires et protègent contre le développement de pathologies auto-immunes. Nous avons observé que le Treg sont recrutés spécéfiquement dans l'environnement tumoral via l'axe de chimiotactisme CCR4/CCL22 suite à la détetion des cellules transformées par les NK et les macrophages. D'autre part, plusieurs publications récentes démontrent un rôle des cellules dendritiques plasmacytoïdes (pDC) dans l'indcution de Treg chez l'homme et la souris. Nos observations montrent que des facteurs solubles sécrétés dans l'environnement tumoral inhibent la fonction clef des pDC, ce qui favorise fortement leur capacité à induire l'expansion de Treg et de T CD4 prodcuteur d'IL-10. Ces cellules T immunosuppressives expriment fortement le récepteur de co-simulation ICOS, prolifèrent in situ, exercent un important pouvoir supresseur sur les autres popuylations T et leur présence est associées à un impact péjoratif sur la survie des patientes. Par l'utilisation de l'Ac bloquant anti-COS 314.8 nous avons démontré le rôle essentiel d'ICOS dans la prolifération des Treg et l'induction de T CD4 sécréteurs d'IL-10 par les pDC dasn les tumeurs, offrant la perspective d'une nouvelle immunothérapie visant à éradqiuer les Treg intra-tumoraux.Tumor immunosbversion favors disease progression and is mediated by increased IL-10 secretion, reduced type-I IFN production and regulatory T cell (Treg) accumulation among CD4+ T cell in breast tumor. We showed that the presence of high number of both Treg and/or plasmacytoid DC (pDC) a subpopulation of antigen presenting celles correlates with poor prognosis in breast carcinoma. We previoously demonstrated that CCR4+ Treg are recruited from the periphery trough CCL22 production by breast tumor cells. Tumor-asssociated Treg (Ta-Treg) are highly activated (GITRhighHDLA-DRhighCD39high), show a selective expression of high levels of ICOS and proliferate in situ (Ki-67+). Tumor associated (Ta-) pDC express a partially activated phenotype but their type-1 interferon (IFN) production is strongly impaired in human tumors. pDc secretion of type-I IFN is linked to their capacity to induce anti-viral and anti-tumor immunity in mice models. We shown that 1) Ta-Treg and Ta-pDC colocalize in breast tumor section and 2) TapDC favor Ta-Treg proliferation and IL-10 secretion by CD4+ T cells in absence of type-I IFN. Ogf importance, targeting ICOS with a neutralizing antibody suppresses Ta-Treg proliferation as well as IL-10 secretion inpDC/CD4+ T cell co-culture, demonstrationg a riole of ICOS-ICOS-L interaction in Ta-Treg proliferation mediated by Ta-pDC. At the end, we report that high ICOS expression in breast tumor sections is associated with reduced patient's overall and disease free survival. Altogether these observations suggest that ICOS in breat cancer may represent a therapeutic target to restore anti-tumor immunit

Les lymphocytes T CD4 régulateurs dans le cancer du sein, recrutement, enrichissement par les cellules dendritiques plasmacytoïdes et impact de l’axe de co-stimulation ICOS/ICOSL

Tumor immunosbversion favors disease progression and is mediated by increased IL-10 secretion, reduced type-I IFN production and regulatory T cell (Treg) accumulation among CD4+ T cell in breast tumor. We showed that the presence of high number of both Treg and/or plasmacytoid DC (pDC) a subpopulation of antigen presenting celles correlates with poor prognosis in breast carcinoma. We previoously demonstrated that CCR4+ Treg are recruited from the periphery trough CCL22 production by breast tumor cells. Tumor-asssociated Treg (Ta-Treg) are highly activated (GITRhighHDLA-DRhighCD39high), show a selective expression of high levels of ICOS and proliferate in situ (Ki-67+). Tumor associated (Ta-) pDC express a partially activated phenotype but their type-1 interferon (IFN) production is strongly impaired in human tumors. pDc secretion of type-I IFN is linked to their capacity to induce anti-viral and anti-tumor immunity in mice models. We shown that 1) Ta-Treg and Ta-pDC colocalize in breast tumor section and 2) TapDC favor Ta-Treg proliferation and IL-10 secretion by CD4+ T cells in absence of type-I IFN. Ogf importance, targeting ICOS with a neutralizing antibody suppresses Ta-Treg proliferation as well as IL-10 secretion inpDC/CD4+ T cell co-culture, demonstrationg a riole of ICOS-ICOS-L interaction in Ta-Treg proliferation mediated by Ta-pDC. At the end, we report that high ICOS expression in breast tumor sections is associated with reduced patient's overall and disease free survival. Altogether these observations suggest that ICOS in breat cancer may represent a therapeutic target to restore anti-tumor immunityLe cancer du sein représente un problème de santé publique. Les efforts déployés pour définir de nouvelles stratégies thérapeutiques ont mis en lumière les mécanismes développés par la tumeur pour inhiber l'instauration d'une réponse immune adaptative efficace. La tumeur favorise la mise en place d'une immunosubversion, caractériisée par la fort infiltration d'une sous-population de lymphocytes T CD4 régulateurs (Treg). Les Treg jouent un rôle central dans les mécanismes de contrôle de réactions pro-inflammatoires et protègent contre le développement de pathologies auto-immunes. Nous avons observé que le Treg sont recrutés spécéfiquement dans l'environnement tumoral via l'axe de chimiotactisme CCR4/CCL22 suite à la détetion des cellules transformées par les NK et les macrophages. D'autre part, plusieurs publications récentes démontrent un rôle des cellules dendritiques plasmacytoïdes (pDC) dans l'indcution de Treg chez l'homme et la souris. Nos observations montrent que des facteurs solubles sécrétés dans l'environnement tumoral inhibent la fonction clef des pDC, ce qui favorise fortement leur capacité à induire l'expansion de Treg et de T CD4 prodcuteur d'IL-10. Ces cellules T immunosuppressives expriment fortement le récepteur de co-simulation ICOS, prolifèrent in situ, exercent un important pouvoir supresseur sur les autres popuylations T et leur présence est associées à un impact péjoratif sur la survie des patientes. Par l'utilisation de l'Ac bloquant anti-COS 314.8 nous avons démontré le rôle essentiel d'ICOS dans la prolifération des Treg et l'induction de T CD4 sécréteurs d'IL-10 par les pDC dasn les tumeurs, offrant la perspective d'une nouvelle immunothérapie visant à éradqiuer les Treg intra-tumoraux

Snail mediates repression of the Dlk1-Dio3 locus in lung tumor-infiltrating immune cells

The epithelial-mesenchymal transition-inducing transcription factor Snail contributes to tumor progression in different malignancies. In the present study, we used a transcriptomics approach to elucidate the mechanism of Snail-mediated tumor growth promotion in a KrasLSL-G12D/+;p53fl/fl mouse model of lung adenocarcinoma. We discovered that Snail mediated the downregulation of the imprinted Dlk1-Dio3 locus, a complex genomic region containing protein-coding genes and non-coding RNAs that has been linked to tumor malignancy in lung cancer patients. The Dlk1- Dio3 locus repression mediated by Snail was found to occur specifically in several populations of tumor-infiltrating immune cells. It could be reproduced in primary splenocytes upon ex vivo culture with conditioned medium from Snail-expressing cancer cell lines, which suggests that a Snail-induced soluble factor secreted by the cancer cells mediates the Dlk1-Dio3 locus repression in immune cells, particularly in lymphocytes. Our findings furthermore point towards the contribution of Snail to an inflammatory tumor microenvironment, which is in line with our previous report of the Snail-mediated recruitment of pro-tumorigenic neutrophils to the lung tumors. This underlines an important role for Snail in influencing the immune compartment of lung tumors and thus contributing to disease progression

Intrinsic features of the cancer cell as drivers of immune checkpoint blockade response and refractoriness

International audienceImmune checkpoint blockade represents the latest revolution in cancer treatment by substantially increasing patients’ lifetime and quality of life in multiple neoplastic pathologies. However, this new avenue of cancer management appeared extremely beneficial in a minority of cancer types and the sub-population of patients that would benefit from such therapies remain difficult to predict. In this review of the literature, we have summarized important knowledge linking cancer cell characteristics with the response to immunotherapy. Mostly focused on lung cancer, our objective was to illustrate how cancer cell diversity inside a well-defined pathology might explain sensitivity and refractoriness to immunotherapies. We first discuss how genomic instability, epigenetics and innate immune signaling could explain differences in the response to immune checkpoint blockers. Then, in a second part we detailed important notions suggesting that altered cancer cell metabolism, specific oncogenic signaling, tumor suppressor loss as well as tight control of the cGAS/STING pathway in the cancer cells can be associated with resistance to immune checkpoint blockade. At the end, we discussed recent evidences that could suggest that immune checkpoint blockade as first line therapy might shape the cancer cell clones diversity and give rise to the appearance of novel resistance mechanisms

Low STING expression in a transplantable KrasG12D/P53ko lung cancer model contributes to SiglecF+ neutrophil and CD103+Treg accumulation in tumors

Lung cancer is the leading cause of mortality by cancer worldwide. Non-small cell lung cancer is the most common type of lung cancer and mutations in the KRAS gene are frequently found in this pathology. While immune checkpoint inhibitors are providing new hope for lung cancer care, only a subset of patients show durable benefit from these new therapies designed to drive an efficient anti-tumor immune response. Hence, it is crucial to better understand the mechanisms through which the tumor immune microenvironment is established in lung tumors. Using bioinformatics, we observed that high expression of the STimulator of INterferon Gene (STING) associates with a longer overall survival specifically in KRAS mutant cancer patients. In lung cancer cell lines, STING expression is linked to interferon response and epithelial-to-mesenchymal transition. Because STING activation in immune cells of the tumor microenvironment using specific agonists is an emerging strategy to trigger an anti-tumor immune response, we took advantage of two transplantable models of Kras driven lung cancer, expressing high or low levels of STING, to investigate the function of STING directly in cancer cells in vivo. We observed that high-STING expression and constitutive STING signaling were critical for transplanted tumor formation rather than playing a major role in tumor immunogenicity. Besides, low-STING expression in cancer cells is associated with an immunosuppressive tumor microenvironment characterized by the accumulation of tumor promoting SiglecF+ neutrophils and CD103+ regulatory T cells. In that model, knocking out STING increased the early response to anti-PD1 treatment. We conclude that low-STING expression in cancer cells might confer them an independence from pro-inflammatory signals and a greater immunosuppressive capability and aggressiveness

ICOS is associated with poor prognosis in breast cancer as it promotes the amplification of immunosuppressive CD4+T cells by plasmacytoid dendritic cells

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Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma

Background Activin-A, a transforming growth factor β family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear. Methods We analyzed the expression of the Activin-A encoding gene INHBA in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of BRAF -driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed INHBA expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models. Results We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of BRAF status by inhibiting CD8 + T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/ INHBA expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models. Conclusions Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.info:eu-repo/semantics/publishe

Single-cell high-dimensional imaging mass cytometry: one step beyond in oncology

International audienceSolid tumors have a dynamic ecosystem in which malignant and non-malignant (endothelial, stromal, and immune) cell types constantly interact. Importantly, the abundance, localization, and functional orientation of each cell component within the tumor microenvironment vary significantly over time and in response to treatment. Such intratumoral heterogeneity influences the tumor course and its sensitivity to treatments. Recently, high-dimensional imaging mass cytometry (IMC) has been developed to explore the tumor ecosystem at the single-cell level. In the last years, several studies demonstrated that IMC is a powerful tool to decipher the tumor complexity. In this review, we summarize the potential of this technology and how it may be useful for cancer research (from preclinical to clinical studies)