Genetically engineered mouse models of cancer reveal new insights about the antitumor immune response

Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Current opinion in immunology (Impact Factor: 7.48). 03/2013; 25(2). DOI: 10.1016/j.coi.2013.02.005
Source: PubMed


Cancer is a complex disease that can originate in virtually all the tissues of the body, and tumors progress through many different stages during their development. While genetic mutations in the emerging cancer cells drive this disease, it has become increasingly clear that cancer development is strongly influenced by the surrounding microenvironment. Cells of the immune system are critical components of this extrinsic network of cancer regulators, contributing significantly to the microenvironment of most cancers and either promoting or inhibiting the initiation and progression of this disease. Genetically engineered mouse (GEM) mouse models of spontaneous cancer are starting to shape our understanding of how antitumor T cells may act to prevent or inhibit cancer progression in some settings and not others. Lessons learned from investigating spontaneous mouse cancer models have important implications for directing clinical efforts that attempt to direct a cancer patient's immune system to eradicate their disease.

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    • "Tumors in GEMMs develop from untransformed cells in their native microenvironment and, importantly, in the presence of a fully functional immune system. However, tumors in GEMMs are often poorly immunogenic, and consequentially, the use of GEMMs for tumor immunology studies has lagged (DuPage and Jacks, 2013). We previously programmed autochthonous sarcomas and lung adenocarcinomas in ''KP'' (Kras Lox-STOP-Lox(LSL)-G12D Trp53 flox/flox ) mice to express ''LucOS,'' firefly luciferase fused to a portion of ovalbumin (ova, encoding the potent T cell OT-I and OT-II antigens ) and the antigenic 2C peptide (DuPage et al., 2011; DuPage et al., 2012). "
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    ABSTRACT: Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 08/2015; DOI:10.1016/j.immuni.2015.08.006 · 21.56 Impact Factor
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    • "PRISM is a tool that provides the opportunity to observe the effects of these mutations on the interactions. Overall, 879 "missense" and "coding silent" mutations from COSMIC database [49,50] are mapped onto 29 target proteins (40 target PDB structures) in the IL-10 centered network (Table 1 and Additional file 3). Each of the interactions of these 29 target proteins can be studied for observing the effects of mutations that are on the interfaces of the predicted models. "
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    ABSTRACT: Background Inflammation has significant roles in all phases of tumor development, including initiation, progression and metastasis. Interleukin-10 (IL-10) is a well-known immuno-modulatory cytokine with an anti-inflammatory activity. Lack of IL-10 allows induction of pro-inflammatory cytokines and hinders anti-tumor immunity, thereby favoring tumor growth. The IL-10 network is among the most important paths linking cancer and inflammation. The simple node-and-edge network representation is useful, but limited, hampering the understanding of the mechanistic details of signaling pathways. Structural networks complete the missing parts, and provide details. The IL-10 structural network may shed light on the mechanisms through which disease-related mutations work and the pathogenesis of malignancies. Results Using PRISM (a PRotein Interactions by Structural Matching tool), we constructed the structural network of IL-10, which includes its first and second degree protein neighbor interactions. We predicted the structures of complexes involved in these interactions, thereby enriching the available structural data. In order to reveal the significance of the interactions, we exploited mutations identified in cancer patients, mapping them onto key proteins of this network. We analyzed the effect of these mutations on the interactions, and demonstrated a relation between these and inflammation and cancer. Our results suggest that mutations that disrupt the interactions of IL-10 with its receptors (IL-10RA and IL-10RB) and α2-macroglobulin (A2M) may enhance inflammation and modulate anti-tumor immunity. Likewise, mutations that weaken the A2M-APP (amyloid precursor protein) association may increase the proliferative effect of APP through preventing β-amyloid degradation by the A2M receptor, and mutations that abolish the A2M-Kallikrein-13 (KLK13) interaction may lead to cell proliferation and metastasis through the destructive effect of KLK13 on the extracellular matrix. Conclusions Prediction of protein-protein interactions through structural matching can enrich the available cellular pathways. In addition, the structural data of protein complexes suggest how oncogenic mutations influence the interactions and explain their potential impact on IL-10 signaling in cancer and inflammation.
    BMC Genomics 05/2014; 15 Suppl 4(Suppl 4):S2. DOI:10.1186/1471-2164-15-S4-S2 · 3.99 Impact Factor
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    ABSTRACT: Unlabelled: Infiltration of human melanomas with cytotoxic immune cells correlates with spontaneous type I IFN activation and a favorable prognosis. Therapeutic blockade of immune-inhibitory receptors in patients with preexisting lymphocytic infiltrates prolongs survival, but new complementary strategies are needed to activate cellular antitumor immunity in immune cell-poor melanomas. Here, we show that primary melanomas in Hgf-Cdk4(R24C) mice, which imitate human immune cell-poor melanomas with a poor outcome, escape IFN-induced immune surveillance and editing. Peritumoral injections of immunostimulatory RNA initiated a cytotoxic inflammatory response in the tumor microenvironment and significantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibody-mediated blockade of the IFN-induced immune-inhibitory interaction between PD-L1 and PD-1 receptors further prolonged the survival. These results highlight important interconnections between type I IFNs and immune-inhibitory receptors in melanoma pathogenesis, which serve as targets for combination immunotherapies. Significance: Using a genetically engineered mouse melanoma model, we demonstrate that targeted activation of the type I IFN system with immunostimulatory RNA in combination with blockade of immune-inhibitory receptors is a rational strategy to expose immune cell-poor tumors to cellular immune surveillance.
    Cancer Discovery 03/2014; 4(6). DOI:10.1158/2159-8290.CD-13-0458 · 19.45 Impact Factor
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