Spontaneous rejection of intradermally transplanted non‐engineered tumor cells by neutrophils and macrophages from syngeneic strains of mice

Ibata, Minenori; Takahashi, Takeshi; Shimizu, Tetsunosuke; Inoué, Yoshihiro; Maeda, Shogo; Tashiro-Yamaji, Junko; Okada, Masashi; Ueda, Koji; Kubota, Takeshi; Yoshida, Ryotaro

doi:10.1111/j.1348-0421.2011.00369.x

Cited by 4 publications

(3 citation statements)

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“…For example, recipients IK17 and IK18 exhibited increases in neutrophil, basophil, and eosinophil counts as well as NK and B cell subsets in peripheral blood, which also contained detectable allo-specific antibodies, indicative of a Th2-mediated allo-immune response. This result is consistent with studies indicating that neutrophils produce cytokines that modulate B, T and dendritic cell function [34], [35] and basophils induce B cell proliferation and class switching via secretion of IL4 and IL13 and expression of CD40 ligand [36]. Moreover, eosinophils also reportedly participate in graft rejection particularly in the absence of a CD4 T cell mediated Th1 response [37].…”

Section: Discussionsupporting

confidence: 89%

Allo-Reactivity of Mesenchymal Stem Cells in Rhesus Macaques Is Dose and Haplotype Dependent and Limits Durable Cell Engraftment In Vivo

et al. 2014

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The emerging paradigm that MSCs are immune privileged has fostered the use of “off-the-shelf” allogeneic MSC-based therapies in human clinical trials. However, this approach ignores studies in experimental animals wherein transplantation of MSCs across MHC boundaries elicits measurable allo-immune responses. To determine if MSCs are hypo-immunogeneic, we characterized the immune response in rhesus macaques following intracranial administration of allogeneic vs. autologous MSCs. This analysis revealed unambiguous evidence of productive allo-recognition based on expansion of NK, B and T cell subsets in peripheral blood and detection of allo-specific antibodies in animals administered allogeneic but not autologous MSCs. Moreover, the degree of MHC class I and II mismatch between the MSC donor and recipient significantly influenced the magnitude and nature of the allo-immune response. Consistent with these findings, real-time PCR analysis of brain tissue from female recipients administered varying doses of male, allogeneic MSCs revealed a significant inverse correlation between MSC engraftment levels and cell dose. Changes in post-transplant neutrophil and lymphocyte counts also correlated with dose and were predictive of overall MSC engraftment levels. However, secondary antigen challenge failed to elicit a measurable immune response in allogeneic recipients. Finally, extensive behavior testing of animals revealed no main effect of cell dose on motor skills, social development, or temperament. Collectively, these data indicate that allogeneic MSCs are weakly immunogenic when transplanted across MHC boundaries in rhesus macaques and this negatively impacts durable engraftment levels. Therefore the use of unrelated donor MSCs should be carefully evaluated in human patients.

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Section: Discussionsupporting

confidence: 89%

Allo-Reactivity of Mesenchymal Stem Cells in Rhesus Macaques Is Dose and Haplotype Dependent and Limits Durable Cell Engraftment In Vivo

et al. 2014

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“…Earlier studies described the rejection of tumor cells after transient growth or without growth by neutrophils and macrophages (not tumor-associated macrophages) [ 80 ]. In this and other cases, rejection depended on the local availability (secretion or introduction) of multiple cytokines (IFN-γ, IL-2, IL-4, IL-7, IL-12, TNF-γ, GM CSF, and IFN-γ/β) [ 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ]. Much attention had been drawn to type I IFNs constituting the first line of defense against cancer cells [ 88 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of the Reverse Transcriptase Domain of Telomerase Reverse Transcriptase Induces Lytic Cellular Response in DNA-Immunized Mice and Limits Tumorigenic and Metastatic Potential of Murine Adenocarcinoma 4T1 Cells

et al. 2020

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Telomerase reverse transcriptase (TERT) is a classic tumor-associated antigen overexpressed in majority of tumors. Several TERT-based cancer vaccines are currently in clinical trials, but immune correlates of their antitumor activity remain largely unknown. Here, we characterized fine specificity and lytic potential of immune response against rat TERT in mice. BALB/c mice were primed with plasmids encoding expression-optimized hemagglutinin-tagged or nontagged TERT or empty vector and boosted with same DNA mixed with plasmid encoding firefly luciferase (Luc DNA). Injections were followed by electroporation. Photon emission from booster sites was assessed by in vivo bioluminescent imaging. Two weeks post boost, mice were sacrificed and assessed for IFN-γ, interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α) production by T-cells upon their stimulation with TERT peptides and for anti-TERT antibodies. All TERT DNA-immunized mice developed cellular and antibody response against epitopes at the N-terminus and reverse transcriptase domain (rtTERT) of TERT. Photon emission from mice boosted with TERT/TERT-HA+Luc DNA was 100 times lower than from vector+Luc DNA-boosted controls. Bioluminescence loss correlated with percent of IFN-γ/IL-2/TNF-α producing CD8+ and CD4+ T-cells specific to rtTERT, indicating immune clearance of TERT/Luc-coexpressing cells. We made murine adenocarcinoma 4T1luc2 cells to express rtTERT by lentiviral transduction. Expression of rtTERT significantly reduced the capacity of 4T1luc2 to form tumors and metastasize in mice, while not affecting in vitro growth. Mice which rejected the tumors developed T-cell response against rtTERT and low/no response to the autoepitope of TERT. This advances rtTERT as key component of TERT-based therapeutic vaccines against cancer.

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“…Importantly, differences in genetic mutations of the transplanted tumors could be excluded as in vitro deletion of the Cyp11b1 gene in tumor organoids by lentiviral Cre transduction resulted in similar reduced tumor growth upon s.c. transplantation. To which extent this immune surveillance is mediated by tumor-specific T lymphocytes, innate immune cells, such as natural killer cells and neutrophils, or a combination thereof [48][49][50], remains to be determined. Clearly, Cyp11b1deficient tumors still grew slower, even in T cell-depleted Rag-deficient mice (Figure 7B), and had increased numbers of infiltrating macrophages, dendritic cells, neutrophils and NK cells (Figure 7I).…”

Section: Discussionmentioning

confidence: 99%

Immune escape of colorectal tumours via local LRH‐1/Cyp11b1‐mediated synthesis of immunosuppressive glucocorticoids

et al. 2023

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Control of tumor development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumors from destruction by the immune system is currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumor development during inflammation-induced mouse model of colorectal cancer. We demonstrate that the local synthesis of immunoregulatory glucocorticoids has dual roles in the regulation of intestinal inflammation and tumor development. In the inflammation phase LRH-1/Nr5A2-regulated and Cyp11b1-mediated intestinal glucocorticoid synthesis prevents tumor development and growth. In established tumors, however, tumor-autonomous Cyp11b1-mediated glucocorticoid synthesis suppresses anti-tumor immune responses and promotes immune escape. Transplantation of glucocorticoid synthesis-proficient colorectal tumor organoids into immunocompetent recipient mice resulted in rapid tumor growth, whereas transplantation of Cyp11b1-deleted and glucocorticoid synthesis-deficient tumor organoids was characterized by reduced tumor growth and increased immune cell infiltration. In human colorectal tumors, high expression of steroidogenic enzymes correlated with the expression of other immune checkpoints and suppressive cytokines, and negatively correlated with overall patients' survival. Thus, LRH-1regulated tumor-specific glucocorticoid synthesis contributes to tumor immune escape and represents a novel potential therapeutic target.

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Spontaneous rejection of intradermally transplanted non‐engineered tumor cells by neutrophils and macrophages from syngeneic strains of mice

Abstract: It is not surprising that tumors arising spontaneously are rarely rejected by T cells, because in general they lack molecules to elicit a primary T-cell response. In fact, cytokine-engineered tumors can induce granulocyte infiltration leading to tumor rejection. In the present study, we i.

Cited by 4 publications

References 45 publications

Allo-Reactivity of Mesenchymal Stem Cells in Rhesus Macaques Is Dose and Haplotype Dependent and Limits Durable Cell Engraftment In Vivo

Allo-Reactivity of Mesenchymal Stem Cells in Rhesus Macaques Is Dose and Haplotype Dependent and Limits Durable Cell Engraftment In Vivo

Expression of the Reverse Transcriptase Domain of Telomerase Reverse Transcriptase Induces Lytic Cellular Response in DNA-Immunized Mice and Limits Tumorigenic and Metastatic Potential of Murine Adenocarcinoma 4T1 Cells

Immune escape of colorectal tumours via local LRH‐1/Cyp11b1‐mediated synthesis of immunosuppressive glucocorticoids

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