Mouse Models of Tumor Immunotherapy

Ngiow, Shin Foong; Loi, Sherene; Thomas, David M.; Smyth, Mark J.

doi:10.1016/bs.ai.2015.12.004

Cited by 33 publications

(26 citation statements)

References 135 publications

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“…1, A and B). To support this finding, we inoculated WT or ACKR4-deficient mice with either intermediate (25 µg) or high (300 µg) doses of 3-methylcholanthrene (MCA) to induce fibrosarcoma (Ngiow et al, 2016). Ackr4 −/− mice displayed a significant survival advantage compared with WT mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

ACKR4 restrains antitumor immunity by regulating CCL21

Whyte

Osman

Kara

et al. 2020

Journal of Experimental Medicine

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Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.

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Section: Resultsmentioning

confidence: 99%

ACKR4 restrains antitumor immunity by regulating CCL21

Whyte

Osman

Kara

et al. 2020

Journal of Experimental Medicine

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“… 13 For mouse models, significant differences have been found between mice and humans in immune system development, activation and response to challenge, in both the innate and adaptive arms. 14 15 For clinical trials, the inconsistencies may be attributed to the lack of clinically relevant cancer models used for human immunotherapy drug testing. 16 Undoubtedly, establishing and developing new HCC-patient-derived xenograft (PDX) model with human tumour immune microenvironment is critical to basic and translational research.…”

Section: Introductionmentioning

confidence: 99%

Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy

Zhao

Shuen

Toh

et al. 2018

Gut

147

143

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ObjectiveAs the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.

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“…Experiment 6: BALB/c mice are widely used in immunological studies (Ngiow, Loi, Thomas, & Smyth, 2016). To study the immune responses of HBcAg-CE12-CQ10 vaccination, 7-week-old male BALB/c mice were divided into three groups (n = 6 per group, four to five mice per cage).…”

Section: Animalsmentioning

confidence: 99%

A bivalent antihypertensive vaccine targeting L‐type calcium channels and angiotensin AT₁ receptors

Wang

Wang³

et al. 2019

British J Pharmacology

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Background and Purpose: Hypertension has been the leading preventable cause of premature death worldwide. The aim of this study was to design a more efficient vaccine against novel targets for the treatment of hypertension.Experimental Approach: The epitope CE12, derived from the human L-type calcium channel (Ca V 1.2), was designed and conjugated with Qβ bacteriophage viruslike particles to test the efficacy in hypertensive animals. Further, the hepatitis B core antigen (HBcAg)-CE12-CQ10 vaccine, a bivalent vaccine based on HBcAg virus-like particles and targeting both human angiotensin AT 1 receptors and Ca V 1.2 channels, was developed and evaluated in hypertensive rodents.Key Results: The Qβ-CE12 vaccine effectively decreased the BP in hypertensive rodents. A monoclonal antibody against CE12 specifically bound to L-type calcium channels and inhibited channel activity. Injection with monoclonal antibody against CE12 effectively reduced the BP in angiotensin II-induced hypertensive mice. The HBcAg-CE12-CQ10 vaccine showed antihypertensive effects in hypertensive mice and relatively superior antihypertensive effects in spontaneously hypertensive rats and ameliorated L-NAME-induced renal injury. In addition, no obvious immunemediated damage or electrophysiological adverse effects were detected.Conclusion and Implications: Immunotherapy against both AT 1 receptors and Ca V 1.2 channels decreased the BP in hypertensive rodents effectively and provided protection against hypertensive target organ damage without obvious feedback activation of renin-angiotensin system or induction of dominant antibodies against the carrier protein. Thus, the HBcAg-CE12-CQ10 vaccine may provide a novel and promising therapeutic approach for hypertension.

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Mouse Models of Tumor Immunotherapy

Cited by 33 publications

References 135 publications

ACKR4 restrains antitumor immunity by regulating CCL21

ACKR4 restrains antitumor immunity by regulating CCL21

Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy

A bivalent antihypertensive vaccine targeting L‐type calcium channels and angiotensin AT₁ receptors

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Mouse Models of Tumor Immunotherapy

Cited by 33 publications

References 135 publications

ACKR4 restrains antitumor immunity by regulating CCL21

ACKR4 restrains antitumor immunity by regulating CCL21

Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy

A bivalent antihypertensive vaccine targeting L‐type calcium channels and angiotensin AT1 receptors

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Product

Resources

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A bivalent antihypertensive vaccine targeting L‐type calcium channels and angiotensin AT₁ receptors