scholarly journals P04.02 A novel cancer immunotherapy combines rMVA-CD40L with tumor targeting antibodies

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A37.1-A37
Author(s):  
M Hinterberger ◽  
J Medina-Echeverz ◽  
M Testori ◽  
M Geiger ◽  
R Giessel ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Targeting ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Positive Impact ◽  
Growth Monitoring ◽  
Adaptive Immune ◽  
Cell Immunity ◽  
Part Time

BackgroundVirus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. In the present study, we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding a Tumor-Associated Antigen (TAA) and the costimulatory CD40L against solid tumors in combination regimes to overcome tumor-induced resistance to immunotherapy.Material and MethodsSubcutaneous murine tumors were induced in C57BL/6 or Balb/c mice using syngeneic tumor cell lines. When tumors were established (60–80 mm3) mice were intravenously injected with rMVA-CD40L. Tumor growth monitoring and immune cell analysis was performed.ResultsTherapeutic treatment with rMVA-CD40L resulted in the control of established tumors in several independent tumor models. This antitumor effect was based on the generation of non-exhausted, systemic tumor-specific cytotoxic CD8+ T cells that was essential for therapeutic efficacy. Strikingly, rMVA-CD40L also induced strong NK cell activation and enhanced cytotoxicity. Moreover, the combination of rMVA-CD40L and tumor targeting antibodies resulted in increased therapeutic antitumor efficacy. This therapeutic combination relied on Fcγ receptor-expressing immune cells as well as on NK cells.ConclusionWe describe a novel and translationally relevant therapeutic synergy between viral vaccination and CD40L costimulation. We show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combining immunotherapeutic regimes, such as TAA targeting antibodies. This finding could have a direct positive impact in therapeutic regimens where TAA targeting antibodies could be employed.Disclosure InformationM. Hinterberger: A. Employment (full or part-time); Significant; Bavarian Nordic. J. Medina-Echeverz: A. Employment (full or part-time); Significant; Bavarian Nordic. M. Testori: A. Employment (full or part-time); Significant; Bavarian Nordic. M. Geiger: A. Employment (full or part-time); Significant; Bavarian Nordic. R. Giessel: A. Employment (full or part-time); Significant; Bavarian Nordic. B. Bathke: A. Employment (full or part-time); Significant; Bavarian Nordic. R. Kassub: A. Employment (full or part-time); Significant; Bavarian Nordic. F. Gräbnitz: A. Employment (full or part-time); Significant; Bavarian Nordic. G. Fiore: A. Employment (full or part-time); Significant; Bavarian Nordic. S. Wennier: A. Employment (full or part-time); Significant; Bavarian Nordic. P. Chaplin: A. Employment (full or part-time); Significant; Bavarian Nordic. M. Suter: A. Employment (full or part-time); Significant; Bavarian Nordic. H. Hochrein: A. Employment (full or part-time); Significant; Bavarian Nordic. H. Lauterbach: A. Employment (full or part-time); Significant; Bavarian Nordic.

scholarly journals Synergistic cancer immunotherapy combines MVA-CD40L induced innate and adaptive immunity with tumor targeting antibodies

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
José Medina-Echeverz ◽  
Maria Hinterberger ◽  
Marco Testori ◽  
Marlene Geiger ◽  
Raphael Giessel ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Targeting ◽  
Cell Activation ◽  
Nk Cell ◽  
Cancer Therapies ◽  
Antitumor Effects ◽  
Innate And Adaptive Immunity ◽  
Adaptive Immune ◽  
Modified Vaccinia Virus Ankara ◽  
Cell Immunity

Abstract Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. Here we report the use of recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors. Therapeutic treatment with rMVA-CD40L-expressing tumor-associated antigens results in the control of established tumors. The expansion of tumor-specific cytotoxic CD8+ T cells is essential for the therapeutic antitumor effects. Strikingly, rMVA-CD40L also induces strong natural killer (NK) cell activation and expansion. Moreover, the combination of rMVA-CD40L and tumor-targeting antibodies results in increased therapeutic antitumor efficacy relying on the presence of Fc receptor and NK cells. We describe a translationally relevant therapeutic synergy between systemic viral vaccination and CD40L costimulation. We show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combination with tumor-targeting antibodies. This immunotherapeutic approach could translate into clinical cancer therapies where tumor-targeting antibodies are employed.

scholarly journals NK-DC Crosstalk in Immunity to Microbial Infection

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Rony Thomas ◽  
Xi Yang
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Microbial Infection ◽  
Adaptive Immune ◽  
Microbial Infections ◽  
Cellular Components ◽  
Secondary Lymphoid Organs ◽  
Dc Maturation

The interaction between natural killer (NK) cell and dendritic cell (DC), two important cellular components of innate immunity, started to be elucidated in the last years. The crosstalk between NK cells and DC, which leads to NK cell activation, DC maturation, or apoptosis, involves cell-cell contacts and soluble factors. This interaction either in the periphery or in the secondary lymphoid organs acts as a key player linking innate and adaptive immune responses to microbial stimuli. This review focuses on the mechanisms of NK-DC interaction and their relevance in antimicrobial responses. We specifically aim to emphasize the ability of various microbial infections to differently influence NK-DC crosstalk thereby contributing to distinct adaptive immune response.

scholarly journals Immune Evasion Mechanism and AXL

2021 ◽  
Vol 11 ◽  
Author(s):  
Hye-Youn Son ◽  
Hwan-Kyu Jeong
Keyword(s):  
Tumor Microenvironment ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Immune Evasion ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Multiple Cancer ◽  
Clinical Prognosis ◽  
Programmed Death

Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and (PD-1/PD-L1) [programmed death (PD) and programmed death-ligand (PD-L1)] in immune checkpoint therapies. AXL is a receptor tyrosine kinase expressed in different types of cancer and in relation to resistance against various anticancer therapeutics due to poor clinical prognosis. AXL and its ligand, i.e., growth arrest-specific 6 (GAS6) proteins, are expressed on many cancer cells, and the GAS6/AXL pathway is reported to promote cancer cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. AXL is an attractive and novel therapeutic target for impairing tumor progression from immune cell contracts in the tumor microenvironment. The GAS6/AXL pathway is also of interest immunologically because it targets fewer antitumor immune responses. In effect, several targeted therapies are selective and nonselective for AXL, which are in preclinical and clinical development in multiple cancer types. Therefore, this review focuses on the role of the GAS6/AXL signaling pathway in triggering the immunosuppressive tumor microenvironment as immune evasion. This includes regulating its composition and activating T-cell exclusion with the immune-suppressive activity of regulatory T cells, which is related to one of the hallmarks of cancer survival. Finally, this article discusses the GAS6/AXL signaling pathway in the context of several immune responses such as NK cell activation, apoptosis, and tumor-specific immunity, especially PD-1/PDL-1 signaling.

scholarly journals The evolutionarily conserved MAPK/Erk signaling promotes ancestral T-cell immunity in fish via c-Myc–mediated glycolysis

2020 ◽  
Vol 295 (10) ◽  
pp. 3000-3016 ◽  
Author(s):  
Xiumei Wei ◽  
Yu Zhang ◽  
Cheng Li ◽  
Kete Ai ◽  
Kang Li ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Nile Tilapia ◽  
Cell Activation ◽  
T Cell Immunity ◽  
Erk Signaling ◽  
Adaptive Immune ◽  
Cell Immunity ◽  
Evolutionarily Conserved

The mitogen-activated protein kinase (MAPK) cascade is an ancient and evolutionarily conserved signaling pathway involved in numerous physiological processes. Despite great advances in understanding MAPK-mediated regulation of adaptive immune responses in mammals, its contribution to T-cell immunity in early vertebrates remains unclear. Herein, we used Nile tilapia (Oreochromis niloticus) to investigate the regulatory roles of MAPK/extracellular signal–regulated kinase (Erk) signaling in ancestral T-cell immunity of jawed fish. We found that Nile tilapia possesses an evolutionarily conserved MAPK/Erk axis that is activated through a classical three-tier kinase cascade, involving sequential phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (Raf), MAPK/Erk kinase 1/2 (Mek1/2), and Erk1/2. In Nile tilapia, MAPK/Erk signaling participates in adaptive immune responses during bacterial infection. Upon T-cell activation, the MAPK/Erk axis is robustly activated, and MAPK/Erk blockade by specific inhibitors severely impairs T-cell activation. Furthermore, signals from MAPK/Erk were indispensable for primordial T cells to proliferate and exert their effector functions. Mechanistically, activation of the MAPK/Erk axis promoted glycolysis via induction of the transcriptional regulator proto-oncogene c-Myc (c-Myc), to ensure the proper activation and proliferation of fish T cells. Our results reveal the regulatory mechanisms of MAPK/Erk signaling in T-cell immunity in fish and highlight a close link between immune signals and metabolic programs. We propose that regulation of T-cell immunity by MAPK/Erk is a basic and sophisticated strategy that evolved before the emergence of the tetrapod lineage. These findings shed light on the evolution of the adaptive immune system.

scholarly journals The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Michal Pyzik ◽  
Eve-Marie Gendron-Pontbriand ◽  
Silvia M. Vidal
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Responses ◽  
Mcmv Infection ◽  
Adaptive Immune ◽  
Innate Lymphocytes ◽  
The Impact

Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses.

scholarly journals A Missing Link: Engagements of Dendritic Cells in the Pathogenesis of SARS-CoV-2 Infections

2021 ◽  
Vol 22 (3) ◽  
pp. 1118
Author(s):  
Abdulaziz Alamri ◽  
Derek Fisk ◽  
Deepak Upreti ◽  
Sam K. P. Kung
Keyword(s):  
Dendritic Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Viral Disease ◽  
Cell Recruitment ◽  
Cross Presentation ◽  
Cell Immunity ◽  
Immune Cell Recruitment

Dendritic cells (DC) connect the innate and adaptive arms of the immune system and carry out numerous roles that are significant in the context of viral disease. Their functions include the control of inflammatory responses, the promotion of tolerance, cross-presentation, immune cell recruitment and the production of antiviral cytokines. Based primarily on the available literature that characterizes the behaviour of many DC subsets during Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), we speculated possible mechanisms through which DC could contribute to COVID-19 immune responses, such as dissemination of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to lymph nodes, mounting dysfunctional inteferon responses and T cell immunity in patients. We highlighted gaps of knowledge in our understanding of DC in COVID-19 pathogenesis and discussed current pre-clinical development of therapies for COVID-19.

scholarly journals Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2500
Author(s):  
Cristina Capuano ◽  
Chiara Pighi ◽  
Simone Battella ◽  
Davide De Federicis ◽  
Ricciarda Galandrini ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Targeting ◽  
Nk Cell ◽  
Intrinsic Resistance ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Cytokines And Chemokines ◽  
Affinity Receptor ◽  
Immunosuppressive Microenvironment

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy.

scholarly journals Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5

2018 ◽  
Vol 116 (3) ◽  
pp. 988-996 ◽  
Author(s):  
Han Wang ◽  
Jianxun Qi ◽  
Shuijun Zhang ◽  
Yan Li ◽  
Shuguang Tan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Complex Structure ◽  
Binding Mode ◽  
Adaptive Immune ◽  
Binding Interface ◽  
Nk Cell Receptors ◽  
D2 Domain ◽  
Hybrid Complex

Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.

scholarly journals Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation

2021 ◽  
Vol 14 (3) ◽  
pp. dmm047589
Author(s):  
Ewelina Dobosz ◽  
Georg Lorenz ◽  
Andrea Ribeiro ◽  
Vivian Würf ◽  
Marta Wadowska ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Immune Responses ◽  
Cell Activation ◽  
Plasma Cells ◽  
Myeloid Cell ◽  
Skin Inflammation ◽  
Adaptive Immune ◽  
Systemic Autoimmunity ◽  
Key Factor ◽  
Old Mice

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

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