The mouse mammary carcinoma 4T1: characterization of the cellular landscape of primary tumours and metastatic tumour foci

duPré, Sally A.; Redelman, Doug; Hunter, Kenneth W.

doi:10.1111/j.1365-2613.2007.00539.x

Cited by 193 publications

(190 citation statements)

References 31 publications

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“…Currently, treatments for irAEs associated with checkpoint blockade have been narrowed to discontinuation of treatment or management by corticosteroids or the addition of infliximab, a chimeric monoclonal antibody against the tumor necrosis factor alpha (TNFa). 52,55 While these treatments are not known to obstruct antitumor responses of immunotherapy, they have no additional benefits to patients currently known. Additionally, immunosuppressive treatments alongside immunotherapy raise concern for opportunistic infections.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, neutrophils have previously been shown to accumulate in pre-metastatic lungs of 4T1 bearing mice in addition to their physiological nature to persist longer in lung tissue. 35,51,52 They have also been implicated in both mouse and human anaphylaxis as well as in behaving as "B-cell helpers" inducing class switch and immunoglobulin production. 38,53 Given these previous data on the preexisting 4T1 microenvironment and our current findings that Gr-1 hi cells increase in lungs with PD-1/PD-L1 blockade, our data suggests that preexisting neutrophils in 4T1 lungs may have played a significant role in airway hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

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Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

et al. 2015

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Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30-60 min after 4-5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing noninflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1 high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

et al. 2015

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“…4T1 cells metastasize aggressively to lung and liver. This model exhibits a profound tumor-derived cytokineinduced host "leukemoid" response, including significant CD11b + Gr-1 + cell expansion, and reflects all steps of breast cancer metastasis development in an immunocompetent host (26)(27)(28)(29).…”

Section: R428 Is a Selective Small-molecule Inhibitor Of Axl Kinasementioning

confidence: 99%

R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Holland¹,

Pan²,

Franci³

et al. 2010

Cancer Research

454

482

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Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors. Cancer Res; 70(4); 1544-54. ©2010 AACR.

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“…1C) (16). Tumor cells were identified as CD45 negative cells in the lungs, as described earlier (17).…”

Section: Cell Isolation Stimulation and Facsmentioning

confidence: 99%

Pulmonary Alveolar Macrophages Contribute to the Premetastatic Niche by Suppressing Antitumor T Cell Responses in the Lungs

Sharma

Chintala

Vadrevu

et al. 2015

The Journal of Immunology

139

135

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In contrast to tumor-associated macrophages, myeloid-derived suppressor cells, or inflammatory monocytes, functions of tissue resident macrophages, including alveolar macrophages (AM), in cancer were not well studied. Using a mouse model of breast cancer, we show that AM promote cancer metastasis to the lungs by suppressing antitumor T cells in this organ. AM accumulated in the premetastatic lungs through complement C5a receptor–mediated proliferation but not through recruitment from the circulation. AM preconditioned by breast tumors inhibited Th1 and favored generation of Th2 cells that had lower tumoricidal activity than Th1 cells. In addition, AM reduced the number and maturation of lung dendritic cells by regulating TGF-β in the lung environment. Depletion of AM reversed immunosuppression imposed by these cells and strengthened local Th1 responses, which significantly reduced lung metastatic burden. C5a receptor deficiency, which also lessens myeloid-derived suppressor cells in the premetastatic niche, synergized with the depletion of AM in preventing metastasis, leading to protection of mice from lung metastases. This study identifies AM as a new component of the premetastatic niche, which is harnessed by tumors to impose immunosuppression, and as a new target for cancer immunotherapies to eliminate or reduce metastasis. Because the lungs are the most common target for hematogenous metastasis, this research offers a plausible explanation for susceptibility of the lungs to cancer metastasis.

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The mouse mammary carcinoma 4T1: characterization of the cellular landscape of primary tumours and metastatic tumour foci

Cited by 193 publications

References 31 publications

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Pulmonary Alveolar Macrophages Contribute to the Premetastatic Niche by Suppressing Antitumor T Cell Responses in the Lungs

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