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Mouse models in oncoimmunology

Key Points

  • The cell-autonomous conception of cancer has been progressively substituted by a view in which interactions of malignant and stromal elements, including immune cells, condition the tumour microenvironment.

  • Transplantable models of mouse cancers implanted in histocompatible, immunocompetent mice have spurred the development of immune checkpoint blockers, as well as the discovery that chemotherapy- and radiotherapy-induced immunogenic cell death stimulates therapeutically relevant anticancer immune responses.

  • Carcinogen-induced models have been instrumental for the discovery of the major principles of anticancer immunoediting, including elimination, equilibrium and escape.

  • Genetically engineered mouse models (GEMMs) are providing fundamental insights into tissue- and context-dependent mechanisms of immune recognition and suppression.

  • Modern genome-editing technologies offer the possibility of exchanging individual mouse genes or entire loci with their human equivalents with the possibility of introducing human elements of the immune and haematological systems into a progressively 'humanized' environment.

  • The combination of immunodeficiencies that affect the mouse immune system, the humanization of the mouse genome by knock in of human genes or loci and the transplantation of human immune cells and tumours provides ever more refined models for oncoimmunology.

Abstract

Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies — each with their specific advantages and difficulties — have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from immune control is an essential feature of cancer, the concept that the long-term effects of conventional cancer treatments mostly rely on the reinstatement of anticancer immune responses and the preclinical development of immunotherapies, including currently approved immune checkpoint blockers. Specific aspects of pharmacological development, as well as attempts to personalize cancer treatments using patient-derived xenografts, require the development of mouse models in which murine genes and cells are replaced with their human equivalents. Such 'humanized' mouse models are being progressively refined to characterize the leukocyte subpopulations that belong to the innate and acquired arms of the immune system as they infiltrate human cancers that are subjected to experimental therapies. We surmise that the ever-advancing refinement of murine preclinical models will accelerate the pace of therapeutic optimization in patients.

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Figure 1: Transplantable mouse cancers.
Figure 2: Carcinogen-induced mouse models of cancer.
Figure 3: Genetically engineered mouse models.
Figure 4: Humanized mouse models.

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Acknowledgements

L.Z. and G.K. are supported by the Institut National Du Cancer (INCA), the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). L.Z. is also supported by the Swiss Institute for Experimental Cancer Research (ISREC), by the Swiss Bridge Foundation, and by IMMUNTRAIN-H2020. J.M.P. is supported by ARC. M.J.S. is supported by National Health and Medical Research Council of Australia Senior Principal Research Fellowship and Project Grants, The Cancer Council of Queensland, and the Cancer Research Institute.

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Correspondence to Laurence Zitvogel or Guido Kroemer.

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Glossary

Targeted therapies

Treatments that specifically target proteins to cause the inhibition or modulation of molecular pathways that are crucial for tumour growth and maintenance.

Gastrointestinal stromal tumours

(GISTs). A common form of mesenchymal neoplasm of the gastrointestinal tract, usually driven by mutations in the KIT gene.

Immunotherapy

Therapy that aims to stimulate or enhance a host immune response against a cause of a disease, resulting in long-term control or eradication of the illness.

Histocompatible

The major histocompatibility locus is shared between cancer cells and their hosts.

C57Bl/6 or BALB/c strains

Standard laboratory strains of mice that are widely used in tumour immunology.

Orthotopically

Engrafting cells into the organ from which they originate. For example, hepatocellular cancer cells are orthortopically injected into the liver.

Immunogenic cell death

(ICD). A cell death modality that is preceded by autophagy and that yields the exposure of immunostimulatory danger signals. ICD of tumour cells, for example, following anthracycline treatment, stimulates immune responses through the activation of antigen-presenting cells.

Natural killer (NK) cells

Cytotoxic cells of the innate immune system that kill target cells in a nonspecific manner (unlike CD8+ T lymphocytes) using molecular cues on the surface to determine that a target cell is not of a healthy status.

'Regressor' tumours

Cancers that, upon their inoculation into histocompatible, immunocompetent mice, first proliferate and then spontaneously disappear.

Cytotoxic T lymphocytes

T lymphocyte immune cells that kill cancer cells or infected cells after specifically recognizing a foreign (that is, viral) or mutated protein presented on class I major histocompatibility complex molecules.

Ploidy

The content of DNA of cells. A normal ploidy (or euploidy) refers to a normal chromosome content, and aneuploid cells have a higher or lower DNA content.

'Progressor' tumours

Tumours that, upon inoculation into mice, grow inexorably, even in hosts that bear a fully competent immune system.

Regulatory T cells

(Treg cells). Subtypes of CD4+ T lymphocytes that potently suppress immune responses through mechanisms such as the production of immunosuppressive cytokines (for example, interleukin-10). Treg cells are well characterized for their expression of the forkhead box P3 (FOXP3) transcription factor.

CD4+ T helper type 1

(TH1). The production of cytokines such as interferon-γ by CD4+ T helper lymphocytes can exert immunostimulatory functions that can direct immune tumour control.

Non-genetically engineered mouse models

(nGEMMs). Genetically controllable mouse models in which oncogene activation or inactivation of tumour suppressors is achieved through stochastic effects.

Dendritic cell vaccines

A process in which dendritic cells are removed from a patient, loaded with tumour material or tumour antigens, matured and then re-infused back into the patient to stimulate T cell responses in vivo.

Xenografts

(Also known as xenotransplants). Living cells, tissues or organs that are transplanted from one species to another (such as human haematopoietic cells or tumours to mouse).

Licensing of NK cells

A process in which natural killer (NK) cells are rendered functionally competent to kill target cells.

CRISPR–Cas9

A defence mechanism against foreign genetic elements (for example, plasmids and phages) found in prokaryotes, involving clustered regularly-interspaced short palindromic repeats (CRISPR; that is, segments of prokaryotic DNA containing short repetitions of base sequences) and the DNA nuclease Cas9. It has huge potential applications in the targeted genome editing of humans, animals and other organisms.

Chimeric antigen receptor (CAR) technology

Engineered expression of CARs on the surface of effector T cells to enable the redirection of T cell specificity. T cells removed from a patient may be modified to express CARs that are specific for the particular form of cancer and then adoptively transferred back to the patient to treat the cancer.

Organoids

In vitro cultured three-dimensional organ buds that show a realistic microanatomy. Such culture systems may be used to create cellular models of human disease.

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Zitvogel, L., Pitt, J., Daillère, R. et al. Mouse models in oncoimmunology. Nat Rev Cancer 16, 759–773 (2016). https://doi.org/10.1038/nrc.2016.91

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