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For the faultless function of the immune system, tight regulation of immune cell activation, immuno-suppression and the strength and efficiency of the immune response is essential. Immune checkpoint (ICP) molecules can amplify or dampen signals that lead to the modulation of specific immune activities. Under physiological conditions, immune checkpoints are essential to prevent autoimmune manifestations and to preserve self-tolerance. They help modulate immune responses by either promoting or inhibiting T-cell activation. However, in the context of cancer, malignant cells can dysregulate the expression of immune checkpoint proteins on immune cells in order to suppress anti-tumor immune responses and to gain immune resistance. Moreover, tumor cells themselves can also express some checkpoints proteins, thereby enabling these cells to externally orchestrate immune regulatory mechanisms. Several recent studies have confirmed that the expression of immune checkpoints could be an important prognostic parameter for cancer development and for patient outcome. Therefore, cancer immunotherapy based on the modulation of immune checkpoint molecules alone, or in combination with conventional tumor therapy (chemo- or/and radiotherapy), is now in focus as a means of developing new therapeutic strategies for different types of cancer. The two well-known molecules – CTLA4 and PD-1 - serve as important examples of such checkpoint proteins of important therapeutic potential. Thus far, inhibitors of CTLA4 and PD-1 have been approved to treat only a limited number of malignancies (e.g. malignant Melanoma, Non-Small Cell Lung Cancer). Many others are currently under investigation and the list of immune checkpoint molecules for potential therapeutic targeting is still growing. However, the clinical response to inhibitors of checkpoint molecules is not sufficient in all cases. Therefore, further studies are needed to improve our knowledge of such immunomodulatory proteins and their associated signaling pathways. Several key signaling pathways which are involved in the regulation of expression of checkpoint molecules in immune cells and in cancer cells have already been identified including MAPK, PI3K, NF-kB, JAKs and STATs. These (and future discovered) signaling pathways could give rise to the development of new strategies for modulating the expression of ICPs and thereby, improving anti-cancer immune responses. The main aim of the Research Topic is to collect novel findings from scientists involved in basic research on immune checkpoints as well as in translational studies investigating the use of checkpoint inhibtors in immunotherapy in experimental settings. We welcome the submission of Review, Mini-Review and Original Research articles that cover the following topics: 1. Molecular mechanisms underlying regulation of ICP expression in immune and/or cancer cells. 2. Characterization of signaling pathways downstream ICP molecules. 3. Cellular responses to ICP blockade. 4. Identification of new compounds interfering with ICP expression and/or signaling. 5. ICP-mediated interactions between cancer cells and immune cells. 6. Functional links between ICP and cytokines/chemokines. 7. Molecular mechanisms of ICP inhibition in the context of experimental cancer immunotherapy.

CTLA-4 (CD152) --- checkpoint blockade --- Immunosuppression --- cancer immunotherapy --- PD-1 (CD279) --- Tumor Microenvironment --- Metabolic checkpoints --- immune checkpoint molecules --- cytotoxic T lymphocytes --- PDL1

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Le système immunitaire joue un rôle essentiel dans la reconnaissance et la destruction des cellules tumorales afin de protéger l’hôte contre le développement de tumeurs. L’immunothérapie repose sur ce principe et a pour objectif de stimuler les fonctions anti- tumorales des cellules immunitaires innées ou adaptatives de l’hôte. Cette thérapie connait un grand succès chez l’Homme avec notamment le développement d’anticorps monoclonaux (Acms), l'immunothérapie cellulaire et les vaccins. Parmi les avancées majeures figure l’utilisation d’Acms inhibiteurs des checkpoints immunitaires. Les checkpoints immunitaires, tels que CTLA-4, PD-1 et PD-L1, sont des protéines transmembranaires. Elles jouent un rôle crucial dans l’inhibition des lymphocytes T afin maintenir l’auto-tolérance et protéger l’hôte des réponses immunitaires excessives. Cependant, ce mécanisme est exploité par les cellules tumorales afin d'échapper à leur destruction par le système immunitaire. Ces Acms vont agir en bloquant ces checkpoints permettant ainsi de restaurer la réponse anti-tumorale des lymphocytes T et d'induire la mort des cellules cancéreuses. L'efficacité de ces traitements a été démontrée dans divers cancers humains, en particulier dans le mélanome, le carcinome rénal et le cancer du poumon non à petites cellules. En médecine vétérinaire, les recherches étant moins avancées, peu d’immunothérapies ont été développées. Récemment, des études ont mis en évidence l’expression de PD-L1 dans plusieurs cancers canins, suggérant leur sensibilité potentielle aux Acms anti-PD-1/PD-L1. Ainsi, une méta-analyse des essais cliniques disponibles chez le chien a été réalisée. Les résultats suggèrent de potentiels bénéfices cliniques avec certaines tumeurs, notamment dans le mélanome malin oral de stade 4. Cependant, malgré ces avancées, des défis persistent, notamment, le faible de taux de réponses objectives et la résistance tumorale au traitement. En conclusion, bien que les Acms inhibiteurs des checkpoints immunitaires offrent des perspectives prometteuses pour le traitement du cancer chez les chiens, des recherches supplémentaires sont nécessaires pour évaluer pleinement leur efficacité, leur sécurité, et d’identifier des biomarqueurs prédictifs de leurs réponses.

Immunothérapie anti-cancéreuse --- Anticorps monoclonaux --- Médecine vétérinaire --- Médecine humaine --- Anticorps anti-CTLA-4 --- Anticorps anti-PD-1 --- Anticorps anti-PD-L1 --- Chiens --- Sciences du vivant > Médecine vétérinaire & santé animale

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The past decade has seen immunotherapy rise to the forefront of cancer treatment. This Special Issue of Cancers aims to elaborate on the latest developments, cutting-edge technologies, and prospects in cancer immunology and immunotherapy. Seventeen exceptional studies, including original contributions and review articles, written by international scientists and physicians, primarily concerning the fields of tumor biology, cancer immunology, therapeutics, and drug development, comprise the main body of this Special Issue.

NKG2D --- CAR T --- IL-7 --- prostate cancer --- cell therapy --- CD19-CAR-T --- B cell aplasia --- KIR --- PD-1 --- inhibitory CAR --- tumor-infiltrating lymphocytes --- tumor microenvironment --- immunotherapy --- NK cells --- cancer stem cells (CSCs) --- antibody-dependent cellular cytotoxicity (ADCC) --- differentiation --- cytotoxicity --- IFN-γ --- osteoclasts --- MICA/B mAb --- DNA methylation --- RNA methylation --- S-adenosylmethionine (SAM) --- cancer --- innate immunity --- adaptive immunity --- T cells --- m6A --- PD-L1 --- resistance --- immune checkpoints --- cancer vaccine --- combination immunotherapy --- TCR diversity --- organ transplantation --- carcinoma --- epidemiologic studies --- immunosuppression --- CTLA-4 --- Treg cells --- immune checkpoint inhibitors --- CD28 --- antigen-presenting cells --- IL15 --- colon cancer --- melanoma --- uveal --- BAP1 --- anti-PD-1 --- anti-CTLA-4 --- TIL --- classical and endemic Kaposi Sarcoma --- systemic treatment --- multi-state modelling --- treatment free interval --- chemotherapy --- interferon --- triple negative breast cancer --- immunomodulation --- bispecific antibody --- sortase A --- chemo-enzymatic approach --- anti-CD20 antibody --- Fab --- BiFab --- colorectal cancer --- dendritic cells --- Atypical Chemokine Receptor 4 (ACKR4) --- T-cell priming --- immune checkpoint blockade --- primary liver cancer --- kynurenine pathway --- immune evasion --- indoleamine 2,3 dioxygenase 1 --- tryptophan 2,3 dioxygenase 2 --- IDO inhibitor --- antigen presenting cells --- n/a

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Dear Readers, Oncolytic Viruses (OV) are self-propagating agents that can selectively induce the lysis of cancer cells while sparing normal tissues. OV-mediated cancer cell death is often immunogenic and triggers robust anticancer immune responses and immunoconversion of tumor microenvironments. This makes oncolytic virotherapy a promising new form of immunotherapy and OVs ideal candidates for combination therapy with other anticancer agents, including other immunotherapeutics. There are more than 40 OVs from nine different families in clinical development and many more at the preclinical stage. Each OV has its own unique characteristics, its pros and cons. Although herpes simplex virus is currently the lead clinical agent, a real champion among the OVs has not yet emerged, justifying the continuous development and optimization of these agents. This book, “Oncolytic Virus Immunotherapy”, summarizes the state-of-the-art and gives a comprehensive overview of the OV arena with a particular focus on new trends, directions, challenges, and opportunities.

Medicine --- Clinical & internal medicine --- oncolytic viruses --- melanoma --- immunotherapy --- checkpoint inhibitors --- combinatory therapy --- reovirus --- oncolytic virus --- adenovirus --- oncolytic --- virotherapy --- targeting --- immunogenic cell death --- αvβ6 integrin --- oncolytic adenovirus --- cancer immunotherapy --- multi-stage --- immunostimulatory --- arming --- HSV-1 --- clinical trials --- newcastle disease virus --- NDV --- cancer --- immune checkpoint inhibitor --- PD-1 --- PD-L1 --- CTLA-4 --- type I interferon --- herpes simplex virus --- retargeted virus --- tropism retargeting --- tumor --- checkpoint inhibitor --- vaccination --- antigen-agnostic vaccination --- HER2 --- parvovirus --- tumor microenvironment --- combination therapy --- glioblastoma --- pancreatic cancer --- colorectal cancer --- measles virus --- vector engineering --- immune checkpoint blockade --- antitumor immune response --- delivery --- genetic modification --- biomarkers --- personalized oncolyticvirotherapy --- class I HLA --- immunosurveillance --- immunoediting --- oncogenic signaling --- RAS --- DNA methyltransferase inhibitor (DNMTi) --- viral mimicry --- epigenetic silencing --- adoptive T cell therapy --- CAR T cell --- pancreatic ductal adenocarcinoma --- vesicular stomatitis virus --- small molecule --- cancer immune therapy --- cancer therapy --- oncolytic viruses --- melanoma --- immunotherapy --- checkpoint inhibitors --- combinatory therapy --- reovirus --- oncolytic virus --- adenovirus --- oncolytic --- virotherapy --- targeting --- immunogenic cell death --- αvβ6 integrin --- oncolytic adenovirus --- cancer immunotherapy --- multi-stage --- immunostimulatory --- arming --- HSV-1 --- clinical trials --- newcastle disease virus --- NDV --- cancer --- immune checkpoint inhibitor --- PD-1 --- PD-L1 --- CTLA-4 --- type I interferon --- herpes simplex virus --- retargeted virus --- tropism retargeting --- tumor --- checkpoint inhibitor --- vaccination --- antigen-agnostic vaccination --- HER2 --- parvovirus --- tumor microenvironment --- combination therapy --- glioblastoma --- pancreatic cancer --- colorectal cancer --- measles virus --- vector engineering --- immune checkpoint blockade --- antitumor immune response --- delivery --- genetic modification --- biomarkers --- personalized oncolyticvirotherapy --- class I HLA --- immunosurveillance --- immunoediting --- oncogenic signaling --- RAS --- DNA methyltransferase inhibitor (DNMTi) --- viral mimicry --- epigenetic silencing --- adoptive T cell therapy --- CAR T cell --- pancreatic ductal adenocarcinoma --- vesicular stomatitis virus --- small molecule --- cancer immune therapy --- cancer therapy

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In this book, we present a compilation of original research articles as well as review articles that are focused on improving our understanding of the molecular and cellular mechanisms by which cancer cells adapt to their microenvironment. These include the interplay between cancer cells and the surrounding microenvironmental cells (e.g., macrophages, tumor-infiltrating lymphocytes and myeloid cells) and microenvironmental environments (e.g., oxidative stress, pH, hypoxia) and the implications of this dynamic interaction to tumor radioresistance, chemoresistance, invasion and metastasis. Finally, the importance and relevance of these findings are translated to cancer therapy.

Medicine --- hypoxia --- macrophages --- colon cancer --- tumor microenvironment --- immune cell infiltration --- prognosis --- feline mammary carcinoma --- PD-1 --- PD-L1 --- CTLA-4 --- TNF-α --- biomarkers --- immunotherapy --- cancer --- histone modification --- inhibitor --- KDM5B --- molecular docking --- repurposing --- cancer acidity --- hyperosmolarity --- cross-presentation --- tumour microenvironment --- syngeneic model --- prostate cancer --- radiotherapy --- preclinical modelling --- myeloid-derived suppressor cells --- biomarker --- stroma --- cancer-associated fibroblast (CAF) --- extracellular matrix (ECM) --- cytokine/chemokine --- growth factors --- pro- and anti-tumor immune cells --- immunomodulatory roles --- radiotherapy dose fractionation --- radioresistance --- radiosensitivity --- breast cancer --- S100A10 (p11) --- tumor growth --- tumor progression --- metastasis --- carcinoma --- mammary gland --- triple negative --- pre-metastatic niche --- pro-inflammatory cytokines --- clinical trials --- evolutionary therapy --- darwinian evolution --- cancer cells subpopulations --- diclofenac --- koningic acid --- spheroid --- 3D co-culture --- microenvironment --- resistance --- myeloid cells --- cancer development --- molecular subtypes of pancreatic cancer --- chemotherapy response --- pancreatic stellate cells --- regulatory T cells --- tumor-associated macrophages --- myeloid derived suppressor cells --- glioblastoma (GB) --- Hypoxia Inducible Factor (HIF) --- glioma stem cells (GSC) --- oxidative stress --- reactive oxygen species --- plasmin --- plasminogen --- S100A10 --- uPA --- uPAR --- PAI-1 --- PAI-2 --- cancer stem cells --- cancer recurrence --- therapeutic resistance --- signaling pathways --- targeted therapy --- head and neck cancer --- lung cancer --- bladder cancer --- hypoxia --- macrophages --- colon cancer --- tumor microenvironment --- immune cell infiltration --- prognosis --- feline mammary carcinoma --- PD-1 --- PD-L1 --- CTLA-4 --- TNF-α --- biomarkers --- immunotherapy --- cancer --- histone modification --- inhibitor --- KDM5B --- molecular docking --- repurposing --- cancer acidity --- hyperosmolarity --- cross-presentation --- tumour microenvironment --- syngeneic model --- prostate cancer --- radiotherapy --- preclinical modelling --- myeloid-derived suppressor cells --- biomarker --- stroma --- cancer-associated fibroblast (CAF) --- extracellular matrix (ECM) --- cytokine/chemokine --- growth factors --- pro- and anti-tumor immune cells --- immunomodulatory roles --- radiotherapy dose fractionation --- radioresistance --- radiosensitivity --- breast cancer --- S100A10 (p11) --- tumor growth --- tumor progression --- metastasis --- carcinoma --- mammary gland --- triple negative --- pre-metastatic niche --- pro-inflammatory cytokines --- clinical trials --- evolutionary therapy --- darwinian evolution --- cancer cells subpopulations --- diclofenac --- koningic acid --- spheroid --- 3D co-culture --- microenvironment --- resistance --- myeloid cells --- cancer development --- molecular subtypes of pancreatic cancer --- chemotherapy response --- pancreatic stellate cells --- regulatory T cells --- tumor-associated macrophages --- myeloid derived suppressor cells --- glioblastoma (GB) --- Hypoxia Inducible Factor (HIF) --- glioma stem cells (GSC) --- oxidative stress --- reactive oxygen species --- plasmin --- plasminogen --- S100A10 --- uPA --- uPAR --- PAI-1 --- PAI-2 --- cancer stem cells --- cancer recurrence --- therapeutic resistance --- signaling pathways --- targeted therapy --- head and neck cancer --- lung cancer --- bladder cancer