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Reproductive Medicine and Biology Jan 2020The testis is specific in that it produces haploid germ cells of which autoantigens newly appear long after the neonatal immune tolerance. Under normal condition, these... (Review)
Review
BACKGROUND
The testis is specific in that it produces haploid germ cells of which autoantigens newly appear long after the neonatal immune tolerance. Under normal condition, these autoantigens are protected by the blood-testis barrier formed by Sertoli cells. Thus, the testis is an immunologically privileged site where haploid cells are protected from autoimmune attack.
METHODS
The immunological microenvironment in the testis was experimentally investigated using mice and rats.
MAIN FINDINGS
Not only the blood-testis barrier but also various immuno-suppressive factors are involved in the immune-privileged testis. Indeed, germ cells transplanted into the xenogeneic seminiferous tubules could proliferate and differentiate with no aid of artificial immunosuppression. On the other hand, autoimmune orchitis could be experimentally produced by various methods of immunization with syngeneic or xenogeneic germ cell antigens.
CONCLUSION
Our results indicate that the testis is immunologically privileged but also immunologically fragile organ. Therefore, the dual nature is critical for immunoregulation of testicular function.
PubMed: 31956282
DOI: 10.1002/rmb2.12293 -
Cancer Research Communications May 2022Tumor biology is determined not only by immortal cancer cells but also by the tumor microenvironment consisting of noncancerous cells and extracellular matrix, together...
UNLABELLED
Tumor biology is determined not only by immortal cancer cells but also by the tumor microenvironment consisting of noncancerous cells and extracellular matrix, together they dictate the pathogenesis and response to treatments. Tumor purity is the proportion of cancer cells in a tumor. It is a fundamental property of cancer and is associated with many clinical features and outcomes. Here we report the first systematic study of tumor purity in patient-derived xenograft (PDX) and syngeneic tumor models using next-generation sequencing data from >9,000 tumors. We found that tumor purity in PDX models is cancer specific and mimics patient tumors, with variation in stromal content and immune infiltration influenced by immune systems of host mice. After the initial engraftment, human stroma in a PDX tumor is quickly replaced by mouse stroma, and tumor purity then stays stable in subsequent transplantations and increases only slightly by passage. Similarly, in syngeneic mouse cancer cell line models, tumor purity also turns out to be an intrinsic property with model and cancer specificities. Computational and pathology analysis confirmed the impact on tumor purity by the diverse stromal and immune profiles. Our study deepens the understanding of mouse tumor models, which will enable their better and novel uses in developing cancer therapeutics, especially ones targeting tumor microenvironment.
SIGNIFICANCE
PDX models are an ideal experimental system to study tumor purity because of its distinct separation of human tumor cells and mouse stromal and immune cells. This study provides a comprehensive view of tumor purity in 27 cancers in PDX models. It also investigates tumor purity in 19 syngeneic models based on unambiguously identified somatic mutations. It will facilitate tumor microenvironment research and drug development in mouse tumor models.
Topics: Humans; Animals; Mice; Xenograft Model Antitumor Assays; Neoplasms; Immune System; Tumor Microenvironment
PubMed: 36875715
DOI: 10.1158/2767-9764.CRC-21-0126 -
Frontiers in Cell and Developmental... 2024This review systematically describes the application of mouse models in studying cutaneous T-cell lymphoma (CTCL), a complex hematological neoplasm. It highlights the... (Review)
Review
This review systematically describes the application of mouse models in studying cutaneous T-cell lymphoma (CTCL), a complex hematological neoplasm. It highlights the diverse research approaches essential for understanding CTCL's intricate pathogenesis and evaluating potential treatments. The review categorizes various mouse models, including xenograft, syngeneic transplantation, and genetically engineered mouse models (GEMMs), emphasizing their contributions to understanding tumor-host interactions, gene functions, and studies on drug efficacy in CTCL. It acknowledges the limitations of these models, particularly in fully replicating human immune responses and early stages of CTCL. The review also highlights novel developments focusing on the potential of skin-targeted GEMMs in studying natural skin lymphoma progression and interactions with the immune system from onset. In conclusion, a balanced understanding of these models' strengths and weaknesses are essential for accelerating the deciphering of CTCL pathogenesis and developing treatment methods. The GEMMs engineered to target specifically skin-homing CD4 T cells can be the next top mouse models that pave the way for exploring the effects of CTCL-related genes.
PubMed: 38665428
DOI: 10.3389/fcell.2024.1372881 -
Proceedings of the National Academy of... Jun 2023Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation...
Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were "permanently eradicated" in a genetically engineered tamoxifen-inducible Treg-cell-specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the chemokine (C-C motif) ligand (Ccl) 19/Ccl21/chemokine (C-C motif) receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C motif chemokine ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and natural killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish preestablished breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3-deleted Tregs represents an approach to completely block tumor growth and recurrence without the autoimmune side effects that typically accompany immune checkpoint modulators.
Topics: Animals; Female; Male; Mice; Breast Neoplasms; Ligands; Mammary Neoplasms, Animal; Mice, Knockout; Nuclear Receptor Coactivator 3; T-Lymphocytes, Regulatory; Tamoxifen
PubMed: 37253006
DOI: 10.1073/pnas.2221707120 -
Cell Reports Jul 2023Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian...
Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2 CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2 tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer.
Topics: Female; Humans; Animals; Mice; Anti-Mullerian Hormone; Ovarian Neoplasms; Peptide Hormones; Mice, Transgenic; Receptors, Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 37453057
DOI: 10.1016/j.celrep.2023.112730 -
Frontiers in Oncology 2023
PubMed: 37483498
DOI: 10.3389/fonc.2023.1243534 -
Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma.Neuro-oncology Advances 2022Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel...
BACKGROUND
Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate preclinical immunotherapeutic research, immunocompetent mouse models that accurately reflect the unique genetic, anatomical, and histological features of DMG patients are warranted.
METHODS
We established cell cultures from primary DMG mouse models (C57BL/6) that were generated by brainstem targeted intra-uterine electroporation (IUE). We subsequently created allograft DMG mouse models by orthotopically implanting these tumor cells into syngeneic mice. Immunohistochemistry and -fluorescence, mass cytometry, and cell-viability assays were then used to verify that these murine tumors recapitulated human DMG.
RESULTS
We generated three genetically distinct allograft models representing histone 3 wildtype (H3) and K27M-mutant DMG (H3.3 and H3.1). These allograft models recapitulated the histopathologic phenotype of their human counterparts, including their diffuse infiltrative growth and expression of DMG-associated antigens. These murine pontine tumors also exhibited an immune microenvironment similar to human DMG, characterized by considerable myeloid cell infiltration and a paucity of T-lymphocytes and NK cells. Finally, we show that these murine DMG cells display similar sensitivity to histone deacetylase (HDAC) inhibition as patient-derived DMG cells.
CONCLUSIONS
We created and validated an accessible method to generate immunocompetent allograft models reflecting different subtypes of DMG. These models adequately recapitulated the histopathology, immune microenvironment, and therapeutic response of human DMG, providing useful tools for future preclinical studies.
PubMed: 35733514
DOI: 10.1093/noajnl/vdac079 -
Journal of Hematology & Oncology Mar 2023The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance....
BACKGROUND
The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.
METHODS
We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.
RESULTS
We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b Gr-1 cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes.
CONCLUSIONS
These findings suggest a distinct vulnerability of ITGB4 tumors for MDSC-directed immunotherapies.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Chemokines; Endothelial Cells; Integrin beta4; Myeloid-Derived Suppressor Cells; Neoplasms; P-Selectin; Tumor Microenvironment
PubMed: 36932441
DOI: 10.1186/s13045-023-01413-9 -
Communications Biology Nov 2023Ovarian cancers exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate human disease are critical to develop new therapeutic...
Ovarian cancers exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate human disease are critical to develop new therapeutic approaches. Syngeneic mouse models allow for the generation of tumours comprising the full repertoire of non-malignant cell types but have expanded in number, varying in the cell type of origin, method for transformation, and ultimately, the properties of the tumours they produce. Here we have performed a comparative analysis of high-grade serous ovarian cancer models based on transcriptomic profiling of 22 cell line models, and intrabursal and intraperitoneal tumours from 12. Among cell lines, we identify distinct signalling activity, such as elevated inflammatory signalling in STOSE and OVE16 models, and MAPK/ERK signalling in ID8 and OVE4 models; metabolic differences, such as reduced glycolysis-associated expression in several engineered ID8 subclones; and relevant functional properties, including differences in EMT activation, PD-L1 and MHC class I expression, and predicted chemosensitivity. Among tumour samples, we observe increased variability and stromal content among intrabursal tumours. Finally, we predict differences in the microenvironment of ID8 models engineered with clinically relevant mutations. We anticipate that this work will serve as a valuable resource, providing new insight to help select models for specific experimental objectives.
Topics: Animals; Mice; Humans; Female; Ovarian Neoplasms; Gene Expression Profiling; Signal Transduction; Tumor Microenvironment
PubMed: 37957414
DOI: 10.1038/s42003-023-05529-z -
Scientific Reports Jan 2021Immune cells play critical functions in cancer, and mice with intact immune systems are vital to understanding tumor immunology. Both genetically engineered mouse models...
Immune cells play critical functions in cancer, and mice with intact immune systems are vital to understanding tumor immunology. Both genetically engineered mouse models (GEMMs) and syngeneic cell transplant approaches use immunocompetent mice to define immune-dependent events in tumor development and progression. Due to their rapid and reproducible nature, there is expanded interest in developing new syngeneic tools from established primary tumor models. However, few studies have examined the extent that syngeneic tumors reflect the immune profile of their originating primary models. Here, we describe comprehensive immunophenotyping of two well-established GEMMs and four new syngeneic models derived from these parental primary tumors. To our knowledge, this is the first systematic analysis comparing immune landscapes between primary and orthotopic syngeneic tumors. These models all use the same well-defined human-relevant driver mutations, arise at identical orthotopic locations, and are generated in mice of the same background strain. This allows for a direct and focused comparison of tumor immune landscapes in carefully controlled mouse models. We identify key differences between the immune infiltrate of GEMM models and their corresponding syngeneic tumors. Most notable is the divergence of T cell populations, with different proportions of CD8+ T cells and regulatory T cells across several models. We also observe immune variation across syngeneic tumors derived from the same primary model. These findings highlight the importance of immune variance across mouse modeling approaches, which has strong implications for the design of rigorous and reproducible translational studies.
Topics: Animals; Disease Models, Animal; Humans; Immunity; Mice; Neoplasms; Proto-Oncogene Proteins p21(ras); T-Lymphocytes
PubMed: 33441747
DOI: 10.1038/s41598-020-80216-1