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Cold Spring Harbor Protocols Dec 2021This procedure is designed to enrich and expand antibody-forming cells for use in generating monoclonal antibodies. Gamma-irradiation is used to wipe out the immune...
This procedure is designed to enrich and expand antibody-forming cells for use in generating monoclonal antibodies. Gamma-irradiation is used to wipe out the immune system in a recipient animal, after which spleen cells that have reverted to memory cells are obtained from syngeneic donor animals and transferred to the irradiated animal, allowing the implanted immune cells to take over. This method can produce an 80-fold enrichment of antibody-producing cells over that obtained in the original immunized animal.
Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; Immunization; Mice; Spleen; Vaccination
PubMed: 34853118
DOI: 10.1101/pdb.prot100347 -
Current Oncology (Toronto, Ont.) Jun 2023Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded... (Review)
Review
Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research.
Topics: Humans; Glioma; Immunotherapy
PubMed: 37366911
DOI: 10.3390/curroncol30060428 -
Cancer Prevention Research... Apr 2022In this issue of Cancer Prevention Research, Cecil and colleagues show that nonsteroidal anti-inflammatory drugs (NSAID), celecoxib and naproxen, decrease the expression...
In this issue of Cancer Prevention Research, Cecil and colleagues show that nonsteroidal anti-inflammatory drugs (NSAID), celecoxib and naproxen, decrease the expression of programmed death-ligand 1 (PD-L1) and increase the influx of Type I tumor-infiltrating lymphocytes in colonic tumors. Importantly, both decrease of PD-L1 expression and increase of CD8+ T cells were associated with the inhibition of COX-2/PGE2 pathway in vitro and syngeneic colonic tumor xenograft models. This study clearly suggests that NSAIDs regulate the intratumoral immunity multiple ways, including suppression of expression of immune checkpoint blockade. Thus, NSAIDs should be considered as chemopreventive for patients with PD-L1-positive colonic polyp. See related article, p. 225.
Topics: Anti-Inflammatory Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Colonic Neoplasms; Humans
PubMed: 35373258
DOI: 10.1158/1940-6207.CAPR-22-0052 -
Trends in Cancer Oct 2021Unraveling the multifaceted cellular and physiological processes associated with metastasis is best achieved by using in vivo models that recapitulate the requisite... (Review)
Review
Unraveling the multifaceted cellular and physiological processes associated with metastasis is best achieved by using in vivo models that recapitulate the requisite tumor cell-intrinsic and -extrinsic mechanisms at the organismal level. We discuss the current status of mouse models of metastasis. We consider how mouse models can refine our understanding of the underlying biological and molecular processes that promote metastasis, and we envisage how the application of new technologies will further enhance investigations of metastasis at single-cell resolution in the context of the whole organism. Our view is that investigations based on state-of-the-art mouse models can propel a holistic understanding of the biology of metastasis, which will ultimately lead to the discovery of new therapeutic opportunities.
Topics: Animals; Disease Models, Animal; Mice; Neoplasms
PubMed: 34303648
DOI: 10.1016/j.trecan.2021.06.010 -
Science Immunology Jul 2021Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator ()...
Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator () gene in self-tolerance, we investigated the role of -expressing cells in maternal-fetal tolerance. We report that maternal ablation of -expressing ( ) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either -expressing medullary thymic epithelial cells or extrathymic -expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.
Topics: Animals; Epithelial Cells; Female; Fetal Growth Retardation; Fetus; Immune Tolerance; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Placenta; Pregnancy; Thymus Gland; Transcription Factors; AIRE Protein
PubMed: 34272228
DOI: 10.1126/sciimmunol.abf1968 -
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 -
Journal of Experimental & Clinical... Oct 2023Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes...
BACKGROUND
Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes PDAC are still not fully understood. Regnase-1, an endoribonuclease, regulates immune responses by degrading mRNAs of inflammation-related genes. Herein, we investigated the role of Regnase-1 in PDAC.
METHODS
Clinical significance of intratumor Regnase-1 expression was evaluated by immunohistochemistry in 39 surgically-resected PDAC patients. The functional role of Regnase-1 was investigated by pancreas-specific Regnase-1 knockout mice and Kras-mutant Regnase-1 knockout mice. The mechanistic studies with gene silencing, RNA immunoprecipitation sequencing (RIP-seq) and immune cell reconstitution were performed in human/mouse PDAC cell lines and a syngeneic orthotopic tumor transplantation model of KrasG12D-mutant and Trp53-deficient PDAC cells.
RESULTS
Regnase-1 expression was negatively correlated with the clinical outcomes and an independent predictor of poor relapse-free and overall survival in PDAC patients. Pancreas-specific Regnase-1 deletion in mice promoteed pancreatic cancer with PMN-MDSC infiltration and shortened their survival. A syngeneic orthotopic PDAC model exhibited that Regnase-1 downregulation accelerated tumor progression via recruitment of intratumor CD11b MDSCs. Mechanistically, Regnase-1 directly negatively regulated a variety of chemokines/cytokines important for MDSC recruitment and activation, including CXCL1, CXCL2, CSF2, and TGFβ, in pancreatic cancer cells. We subsequently showed that IL-1β-mediated Regnase-1 downregulation recruited MDSCs to tumor sites and promoted pancreatic cancer progression via mitigation of cytotoxic T lympohocytes-mediated antitumor immunity.
CONCLUSIONS
IL-1b-mediated Regnase-1 downregulation induces MDSCs and promotes pancreatic cancer through the evasion of anticancer immunity.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Down-Regulation; Inflammation; Mice, Knockout; Myeloid-Derived Suppressor Cells; Pancreatic Neoplasms; Ribonucleases
PubMed: 37814340
DOI: 10.1186/s13046-023-02831-w