scholarly journals Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

ILAR Journal ◽  
2018 ◽  
Vol 59 (3) ◽  
pp. 247-262 ◽  
Author(s):  
Nana H Overgaard ◽  
Timothy M Fan ◽  
Kyle M Schachtschneider ◽  
Daniel R Principe ◽  
Lawrence B Schook ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Model Systems ◽  
High Rate ◽  
Host Immune System ◽  
Cancer Immunoediting ◽  
Oncology Research ◽  
Experimental Cancer

Abstract The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E’s, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.

scholarly journals APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

2020 ◽  
Author(s):  
Sophie de Carné Trécesson ◽  
Jesse Boumelha ◽  
Emily K. Law ◽  
Pablo Romero-Clavijo ◽  
Edurne Mugarza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Mouse Models ◽  
Cytosine Deaminase ◽  
Adaptive Immune System ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Tumour Regression ◽  
Host Immune System ◽  
Mutational Burden

ABSTRACTMutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant Kras-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This causes an increase in mutational burden in Kras mutant and p53 deleted (KP) tumours and in carcinogen-induced tumours, but these mutations are sub-clonal and do not lead to sensitivity of the autochthonous tumours to immune interventions. However, when clonal cell lines are derived from these tumours they provide an immunogenic syngeneic transplantation lung cancer model that is sensitive to immunotherapy. The ability of a KRAS-G12C inhibitor to cause regression of these tumours is markedly potentiated by the adaptive immune system, providing an opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

scholarly journals High-dimensional immune-profiling in cancer: implications for immunotherapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000363 ◽  
Author(s):  
Samuel Chuah ◽  
Valerie Chew
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
Positive Impact ◽  
Cell Types ◽  
High Dimensional ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Quality Of Data ◽  
New Information ◽  
Immune Profiling

Immunotherapy is a rapidly growing field for cancer treatment. In contrast to conventional cancer therapies, immunotherapeutic strategies focus on reactivating the immune system to mount an antitumor response. Despite the encouraging outcome in clinical trials, a large proportion of patients still do not respond to treatment and many experience different degrees of immune-related adverse events. Furthermore, it is now increasingly appreciated that even many conventional cancer therapies such as radiotherapy could have a positive impact on the host immune system for better clinical response. Hence, there is a need to better understand tumor immunity in order to design immunotherapeutic strategies, especially evidence-based combination therapies, for improved clinical outcomes. With this aim, cancer research turned its attention to profiling the immune contexture of either the tumor microenvironment (TME) or peripheral blood to uncover mechanisms and biomarkers which might aid in precision immunotherapeutics. Conventional technologies used for this purpose were limited by the depth and dimensionality of the data. Advances in newer techniques have, however, greatly improved the breadth and depth, as well as the quantity and quality of data that can be obtained. The result of these advances is a wealth of new information and insights on how the TME could be affected by various immune cell-types, and how this might in turn impact the clinical outcome of cancer patients . We highlight herein some of the high-dimensional technologies currently employed in immune profiling in cancer and summarize the insights and potential benefits they could bring in designing better cancer immunotherapies.

scholarly journals Single-cell RNA sequencing reveals micro-evolution of the stickleback immune system

2021 ◽  
Author(s):  
Lauren E Fuess ◽  
Daniel I Bolnick
Keyword(s):  
Immune System ◽  
Single Cell ◽  
Immune Cells ◽  
Gasterosteus Aculeatus ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cell Types ◽  
Model Systems ◽  
System Structure ◽  
Ecological Processes

Pathogenic infection is an important driver of many ecological processes. Furthermore, variability in immune function is an important driver of differential infection outcomes. New evidence would suggest that immune variation extends to broad cellular structure of immune systems. However, variability at such broad levels is traditionally difficult to detect in non-model systems. Here we leverage single cell transcriptomic approaches to document signatures of microevolution of immune system structure in a natural system, the three-spined stickleback (Gasterosteus aculeatus). We sampled nine adult fish from three populations with variability in resistance to a cestode parasite, Schistocephalus solidus, to create the first comprehensive immune cell atlas for G. aculeatus. Eight major immune cell types, corresponding to major vertebrate immune cells, were identified. We were also able to document significant variation in both abundance and expression profiles of the individual immune cell types, among the three populations of fish. This variability may contribute to observed variability in parasite susceptibility. Finally, we demonstrate that identified cell type markers can be used to reinterpret traditional transcriptomic data. Combined our study demonstrates the power of single cell sequencing to not only document evolutionary phenomena (i.e. microevolution of immune cells), but also increase the power of traditional transcriptomic datasets.

scholarly journals Preliminary Study of the Effect of Stereotactic Body Radiotherapy (SBRT) on the Immune System in Lung Cancer Patients Unfit for Surgery: Immunophenotyping Analysis

2018 ◽  
Vol 19 (12) ◽  
pp. 3963 ◽  
Author(s):  
Arturo Navarro-Martín ◽  
Isabel Galiana ◽  
Miguel Berenguer Frances ◽  
Jon Cacicedo ◽  
Rut Cañas Cortés ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Cancer Patients ◽  
Stereotactic Body Radiotherapy ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Host Immune System ◽  
Lung Cancer Patients ◽  
Specific Increase ◽  
Relevant Finding

An immunophenotyping analysis was performed in peripheral blood samples from seven patients with lung cancer unfit for surgery treated with stereotactic body radiotherapy (SBRT). The objective was to characterize the effect of SBRT on the host immune system. Four patients received 60 Gy (7.5 Gy × 8) and three 50 Gy (12.5 Gy × 4). Analyses were performed before SBRT, 72 h after SBRT, and at one, three, and six months after the end of SBRT. Of note, there was a specific increase of the immunoactive component of the immune system, with elevation of CD56+highCD16+ natural killer (NK) cells (0.95% at baseline to 1.38% at six months), and a decrease of the immunosuppressive component of the immune system, with decreases of CD4+CD25+Foxp3+CDA5RA− regulatory T cells (4.97% at baseline to 4.46% at six months), granulocytic myeloid-derived suppressor cells (G-MDSCs) (from 66.1% at baseline to 62.6% at six months) and monocytic (Mo-MDSCs) (8.2% at baseline to 6.2% at six months). These changes were already apparent at 72 h and persisted over six months. SBRT showed an effect on systemic immune cell populations, which is a relevant finding for supporting future combinations of SBRT with immunotherapy for treating lung cancer patients.

scholarly journals Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy

2021 ◽  
Vol 22 (21) ◽  
pp. 11726
Author(s):  
Ali R. Jazirehi
Keyword(s):  
T Cells ◽  
Immune System ◽  
Targeted Therapy ◽  
T Cell ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
High Rate ◽  
Host Immune System

Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell receptor (TCR)-engineered T cells aim to increase the ability of the host immune system to recognize and eradicate tumors. ICIs inhibit negative regulatory mechanisms and boost the antitumor activity of the host’s immune system, while targeted therapy directed against aberrant signaling molecules (BRAF and MEK) will block the uncontrolled proliferation and expansion of melanomas. The basis of the TCR-engineered T cell strategy is to transduce host T cells with antigen-specific TCRα/β chains to produce high-affinity T cells for tumor-associated antigens. TCR-transgenic T cells are expanded and activated ex vivo and reinfused into patients to increase the targeting of cancer cells. While these treatments have had varyingly favorable results, their efficacy is limited due to inherent or acquired resistance. Various mechanisms explain melanoma immune-resistance, including the loss or downregulation of the MCH/peptide complex, aberrant activity of signaling pathways, and altered dynamics of apoptotic machinery. Collectively, these mechanisms confer melanoma resistance to apoptotic stimuli delivered by T cells despite a fully functional and effective antitumor immune response. Identification of biomarkers, combination treatment, and the use of CAR T cells are among the approaches that can potentially circumvent melanoma’s resistance to immunotherapy.

scholarly journals Effects of Citrus Fruit Juices and Their Bioactive Components on Inflammation and Immunity: A Narrative Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Elizabeth A. Miles ◽  
Philip C. Calder
Keyword(s):  
Oxidative Stress ◽  
Immune System ◽  
Vitamin C ◽  
Orange Juice ◽  
Immune Cell ◽  
Meta Analysis ◽  
Citrus Fruit ◽  
Fruit Juices ◽  
Model Systems ◽  
Markers Of Inflammation

The immune system provides defence to the host against pathogenic organisms. A weak immune system increases susceptibility to infections and allows infections to become more severe. One component of the immune response is inflammation. Where inflammation is excessive or uncontrolled it can damage host tissues and cause pathology. Limitation of oxidative stress is one means of controlling inflammation. Citrus fruit juices are a particularly good source of vitamin C and folate, which both have roles in sustaining the integrity of immunological barriers and in supporting the function of many types of immune cell including phagocytes, natural killer cells, T-cells and B-cells. Vitamin C is an antioxidant and reduces aspects of the inflammatory response. Important bioactive polyphenols in citrus fruit juices include hesperidin, narirutin and naringin. Hesperidin is a glycoside of hesperetin while narirutin and naringin are glycosides of naringenin. Hesperidin, hesperetin, naringenin, naringin and narirutin have all been found to have anti-inflammatory effects in model systems, and human trials of hesperidin report reductions in inflammatory markers. In humans, orange juice was shown to limit the post-prandial inflammation induced by a high fat-high carbohydrate meal. Consuming orange juice daily for a period of weeks has been reported to reduce markers of inflammation, including C-reactive protein, as confirmed through a recent meta-analysis. A newly emerging topic is whether polyphenols from orange juice have direct anti-viral effects. In summary, micronutrients and other bioactives present in citrus fruit juices have established roles in controlling oxidative stress and inflammation and in supporting innate and acquired immune responses. Trials in humans demonstrate that orange juice reduces inflammation; its effects on innate and acquired immunity require further exploration in well-designed trials in appropriate population sub-groups such as older people.

scholarly journals The Role of miRNAs in Immune Cell Development, Immune Cell Activation, and Tumor Immunity: With a Focus on Macrophages and Natural Killer Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1140 ◽  
Author(s):  
Shi Jun Xu ◽  
Hong Tao Hu ◽  
Hai Liang Li ◽  
Suhwan Chang
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Immune Cell ◽  
Host Immune System ◽  
Stromal Compartment ◽  
Cell Functions

The tumor microenvironment (TME) is the primary arena where tumor cells and the host immune system interact. Bidirectional communication between tumor cells and the associated stromal cell types within the TME influences disease initiation and progression, as well as tumor immunity. Macrophages and natural killer (NK) cells are crucial components of the stromal compartment and display either pro- or anti-tumor properties, depending on the expression of key regulators. MicroRNAs (miRNAs) are emerging as such regulators. They affect several immune cell functions closely related to tumor evasion of the immune system. This review discusses the role of miRNAs in the differentiation, maturation, and activation of immune cells as well as tumor immunity, focusing particularly on macrophages and NK cells.

scholarly journals Cancer-Immunity Cycle and Therapeutic Interventions- Opportunities for Including Pet Dogs With Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Samantha K. Von Rueden ◽  
Timothy M. Fan
Keyword(s):  
Immune System ◽  
Animal Models ◽  
Tumor Formation ◽  
Therapeutic Interventions ◽  
Large Animal ◽  
Host Immune System ◽  
Host Immune Responses ◽  
Large Animal Models ◽  
Cancer Immunity ◽  
Dynamic Series

The tumor-immune interplay represents a dynamic series of events executed by cellular and soluble participants that either promote or inhibit successful tumor formation and growth. Throughout a tumor’s development and progression, the host organism’s immune system reacts by generating anti-cancer defenses through various incremental and combinatorial mechanisms, and this reactive orchestration is termed the cancer-immunity cycle. Success or failure of the cancer-immunity cycle dictates the fate of both host and tumor as winner or loser. Insights into how the tumor and host immune system continuously adapt to each other throughout the lifecycle of the tumor is necessary to rationally develop new effective immunotherapies. Additionally, the evolving nature of the cancer-immunity cycle necessitates therapeutic agility, requiring real-time serial assessment of immunobiologic markers that permits tailoring of therapies to the everchanging tumor immune microenvironment. In order to accelerate advances in the field of immuno-oncology, this review summarizes the steps comprising the cancer-immunity cycle, and underscores key breakpoints in the cycle that either favor cancer regression or progression, as well as shaping of the tumor microenvironment and associated immune phenotypes. Furthermore, specific large animal models of spontaneous cancers that are deemed immunogenic will be reviewed and proposed as unique resources for validating investigational immunotherapeutic protocols that are informed by the cancer-immunity cycle. Collectively, this review will provide a progressive look into the dynamic interplay between tumor and host immune responses and raise awareness for how large animal models can be included for developing combinatorial and sequenced immunotherapies to maximizing favorable treatment outcomes.

scholarly journals Macrophage-Based Combination Therapies as a New Strategy for Cancer Immunotherapy

2021 ◽  
pp. 1-18
Author(s):  
Lin Tian ◽  
Anhua Lei ◽  
Tianyu Tan ◽  
Mengmeng Zhu ◽  
Li Zhang ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Immune Modulation ◽  
Immune Cell ◽  
Genetically Engineered ◽  
M2 Macrophages ◽  
Cell Therapies ◽  
Tumor Microenvironments

<b><i>Background:</i></b> Cells of the immune system can inhibit tumor growth and progression; however, immune cells can also promote tumor cell growth, survival, and angiogenesis as a result of the immunosuppressive microenvironments. In the last decade, a growing number of new therapeutic strategies focused on reversing the immunosuppressive status of tumor microenvironments (TMEs), to reprogram the TME to be normal, and to further activate the antitumor functions of immune cells. Most of the “hot tumors” are encompassed with M2 macrophages promoting tumor growth, and the accumulation of M2 macrophages into tumor islets leads to poor prognosis in a wide variety of tumors. <b><i>Summary:</i></b> Therefore, how to uncover more immunosuppressive signals and to reverse the M2 tumor-associated macrophages (TAMs) to M1-type macrophages is essential for reversing the immunosuppressive state. Except for reeducation of TAMs in the cancer immunotherapy, macrophages as central effectors and regulators of the innate immune system have the capacity of phagocytosis and immune modulation in macrophage-based cell therapies. <b><i>Key Messages:</i></b> We review the current macrophage-based cell therapies that use genetic engineering to augment macrophage functionalities with antitumor activity for the application of novel genetically engineered immune cell therapeutics. A combination of TAM reeducation and macrophage-based cell strategy may bring us closer to achieving the original goals of curing cancer. In this review, we describe the characteristics, immune status, and tumor immunotherapy strategies of macrophages to provide clues and evidences for future macrophage-based immune cell therapies.

scholarly journals The Opportunistic PathogenListeria monocytogenes: Pathogenicity and Interaction with the Mucosal Immune System

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Markus Schuppler ◽  
Martin J. Loessner
Keyword(s):  
Immune System ◽  
Gastrointestinal Tract ◽  
Foodborne Pathogen ◽  
Mucosal Immune System ◽  
Model Systems ◽  
Host Immune System ◽  
Gastrointestinal Microbiota ◽  
Commensal Flora ◽  
Mucosal Surfaces ◽  
Antigenic Load

Listeria monocytogenesis an opportunistic foodborne pathogen causing listeriosis, an often fatal infection leading to meningitis, sepsis, or infection of the fetus and abortion in susceptible individuals. It was recently found that the bacterium can also cause acute, self-limiting febrile gastroenteritis in healthy individuals. In the intestinal tract,L. monocytogenespenetrates the mucosa directly via enterocytes, or indirectly via invasion of Peyer’s patches. Animal models forL. monocytogenesinfection have provided many insights into the mechanisms of pathogenesis, and the development of new model systems has allowed the investigation of factors that influence adaptation to the gastrointestinal environment as well as adhesion to and invasion of the intestinal mucosa. The mucosal surfaces of the gastrointestinal tract are permanently exposed to an enormous antigenic load derived from the gastrointestinal microbiota present in the human bowel. The integrity of the important epithelial barrier is maintained by the mucosal immune system and its interaction with the commensal flora via pattern recognition receptors (PRRs). Here, we discuss recent advances in our understanding of the interaction ofL. monocytogeneswith the host immune system that triggers the antibacterial immune responses on the mucosal surfaces of the human gastrointestinal tract.

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