An immune-active tumor microenvironment favors clinical response to ipilimumab

Ji, Rui-Ru; Chasalow, Scott D.; Wang, Lisu; Hamid, Omid; Schmidt, Henrik; Cogswell, John; Suresh, A.; Berman, David M.; Jure-Kunkel, Maria; Siemers, Nathan O.; Jackson, Jeffrey R.; Shahabi, Vafa

doi:10.1007/s00262-011-1172-6

Cited by 686 publications

(547 citation statements)

References 45 publications

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“…However, when these responses are assessed in the context of the distinct tumor microenvironments observed across the preclinical models, our results are broadly in agreement with clinical findings, which demonstrate an association between CD8 + T-cell infiltration into the tumor and outcome following immune-checkpoint blockade (9,48,49). Indeed, our work also revealed that tumors such as CT26, in which the immune infiltrate contains greater numbers of cytotoxic immune cells such as CD8 + T cells and NK cells, were more responsive to immunecheckpoint blockade than those with comparatively little immune or predominantly immunosuppressive infiltrate.…”

Section: Discussionsupporting

confidence: 80%

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

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Sainson

et al. 2017

Cancer Immunology Research

333

381

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(word count: 239):Murine syngeneic tumor models are critical to novel immuno-based therapy development but the molecular and immunological features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We employed array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor 'inflamed' and 'non-inflamed' tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo.4

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Section: Discussionsupporting

confidence: 80%

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Mosely

Prime

Sainson

et al. 2017

Cancer Immunology Research

333

381

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“…A limiting factor in immune therapy is the insufficient homing of T cells to the tumor site. Many of the new immune therapies either require the presence of pre-existing T cells in the tumor, 12 , 26 , 27 or rely on sufficient tumor homing of tumor specific T cells after peripheral or in vitro activation. 14 , 28 …”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

et al. 2018

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Adoptive cell therapy (ACT) using in vitro expanded tumor infiltrating T lymphocytes (TILs) from biopsy material represents a highly promising treatment of disseminated cancer. A crucial prerequisite for successful ACT is sufficient recruitment of transferred lymphocytes to the tumor site; however, despite infusion of billions of lymphocytes, T cell infiltration into the tumor post ACT is limited. By PCR and Luminex analyses we found that a majority of malignant melanoma (MM) cell lines expressed chemokines CXCL1/Groα, CXCL8/IL-8, CXCL12/SDF-1 and CCL2. Concerning expression of the corresponding receptors on T cells, only the IL-8 receptor, CXCR2, was not expressed on T cells. CXCR2 was therefore expressed in T cells by lentiviral transduction, and shown to lead to ligand specific transwell migration of engineered T cells, as well as increased migration towards MM conditioned medium. In vivo homing was assessed in a xenograft NOG mouse model. Mice with subcutaneous human melanoma were treated with MAGE-A3 specific T cells transduced with either CXCR2 or MOCK. Transducing T cells carrying the MAGE-A3a3a high affinity T cell receptor with CXCR2 increased tumor infiltration. Flow cytometry analysis 7 days after ACT showed a doubling in CD3+ T cells in tumor digest of mice receiving CXCR2 transduced T cells compared to MOCK treated mice, a finding confirmed by immunohistochemistry. In conclusion, our CXCR2 transduced T cells are functional in vitro and transduction with CXCR2 increases in vivo homing of T cells to tumor site.

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“…On the basis of the observation that intratumoural antitumour inflammation is triggered after secretion of IFNγ by infiltrating CD8 + T cells 99 , a profile referred to as the 'T-cell-inflamed tumour microenvironment' has been associated with response to diverse immunotherapies, including vaccines, IL-2, as well as anti-CTLA-4 and anti-PD-1 antibodies [138][139][140][141] . This concept has been applied broadly in melanoma and beyond (in gastric, head and neck, and urothelial cancers), with multiple reports from the 2015 ASCO meeting indicating not only that increasing IFNγ-associated gene-expression scores are predictive of a response to pembrolizumab, but also, perhaps more importantly, that the lack of IFNγ-associated gene expression is very highly correlated with lack of clinical benefit 100,[142][143][144] .…”

Section: Braf-mek-inhibitor Resistance and Biomarkersmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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An immune-active tumor microenvironment favors clinical response to ipilimumab

Abstract: These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.

Cited by 686 publications

References 45 publications

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

Targeted agents and immunotherapies: optimizing outcomes in melanoma

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