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Melanoma: HELP
Articles by John G. Frelinger
Based on 3 articles published since 2010
(Why 3 articles?)

Between 2010 and 2020, J. G. Frelinger wrote the following 3 articles about Melanoma.
+ Citations + Abstracts
1 Article Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. 2015

Mikucki, M E / Fisher, D T / Matsuzaki, J / Skitzki, J J / Gaulin, N B / Muhitch, J B / Ku, A W / Frelinger, J G / Odunsi, K / Gajewski, T F / Luster, A D / Evans, S S. ·Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA. · Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. · Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. · Department of Microbiology and Immunology, University of Rochester Medical Center and the Wilmot Cancer Center, Rochester, New York 14642, USA. · Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. · Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. · Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA. · Comprehensive Cancer Center and Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA. · Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ·Nat Commun · Pubmed #26109379.

ABSTRACT: T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. Chemokines are credited with guiding the multistep recruitment of CD8(+) T cells across tumour vessels. However, the multiplicity of chemokines within tumours has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signalling at effector sites. Here we investigate the hierarchy of chemokine receptor requirements during T-cell trafficking to murine and human melanoma. These studies reveal a non-redundant role for Gαi-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8(+) effectors that is indispensable for therapeutic efficacy. In contrast, functional CCR2 and CCR5 on CD8(+) effectors fail to support trafficking despite the presence of intratumoral cognate chemokines. Taken together, these studies identify CXCR3-mediated trafficking at the tumour vascular interface as a critical checkpoint to effective T-cell-based cancer immunotherapy.

2 Article Local expression of interleukin-2 by B16 melanoma cells results in decreased tumour growth and long-term tumour dormancy. 2013

Gerber, Scott A / Sorensen, Elizabeth W / Sedlacek, Abigail L / Lim, Joanne Y H / Skrombolas, Denise / Frelinger, John G / Lord, Edith M. ·University of Rochester School of Medicine and Dentistry, Department of Microbiology and Immunology, Rochester, NY, USA. Scott_Gerber@urmc.rochester.edu ·Immunology · Pubmed #23198850.

ABSTRACT: The tumour microenvironment is complex containing not only neoplastic cells but also a variety of host cells. The heterogeneous infiltrating immune cells include subsets of cells with opposing functions, whose activities are mediated either directly or through the cytokines they produce. Systemic delivery of cytokines such as interleukin-2 ( IL-2) has been used clinically to enhance anti-tumour responses, but these molecules are generally thought to have evolved to act locally in a paracrine fashion. In this study we examined the effect of local production of IL-2 on the growth and the immune response to B16 melanoma cells. We found that the local production of IL-2 enhances the number of interferon-γ-expressing CD8 T and natural killer cells in the tumour, as well as inducing expression of vascular cell adhesion molecule 1 on tumour vessels. These responses were largely absent in interferon-γ knockout mice. The expression of IL-2 in the tumour microenvironment decreases tumour growth despite also enhancing Foxp3(+)  CD4(+) regulatory T cells and anti-inflammatory cytokines such as IL-10. Higher levels of IL-2 in the tumour microenvironment eliminated the progressive growth of the B16 cells in vivo, and this inhibition was dependent on the presence of either T cells or, to a lesser extent, natural killer cells. Surprisingly however, the B16 tumours were not completely eliminated but instead were controlled for an extended period of time, suggesting that a form of tumour dormancy was established.

3 Article IL-12 suppresses vascular endothelial growth factor receptor 3 expression on tumor vessels by two distinct IFN-gamma-dependent mechanisms. 2010

Sorensen, Elizabeth W / Gerber, Scott A / Frelinger, John G / Lord, Edith M. ·Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA. ·J Immunol · Pubmed #20061409.

ABSTRACT: IL-12 has been shown to be effective in enhancing antitumor responses. However, how IL-12 exerts its antiangiogenic effect is largely unknown. In this study, we elucidate this mechanism using B16 transfected to express IL-12 (B16/IL-12), a system that provides constant, local production of IL-12 within the tumor microenvironment. Intratumoral IL-12 resulted in a significant delay in tumor growth and phenotypic changes in the vasculature. Vessels found within B16 tumors are chaotic and poorly formed and express vascular endothelial growth factor receptor 3 (VEGFR3), a growth factor receptor not expressed on normal adult vessels. However, the vessels within B16/IL-12 tumors have a more normal morphology and do not express VEGFR3. We have shown that IFN-gamma is required for IL-12 to suppress the aberrant expression of VEGFR3. Indeed, the presence of intratumoral IL-12 stimulates the immune system resulting in more IFN-gamma-producing tumor-infiltrating lymphocytes per tumor when compared with parental B16 tumors, which may have a marked effect on control of tumor growth. Interestingly, within B16/IL-12 tumors, T cells are necessary to suppress VEGFR3 expression on tumor vessels. Finally, using IFN-gamma receptor knockout mice in a bone marrow chimera system, we show that the IFN-gamma produced within the tumor suppresses VEGFR3 expression in two ways: 1) acting directly on tumor vessel endothelial cells, and 2) acting on the tumor-infiltrating lymphocytes to indirectly alter endothelial cells' VEGFR3 expression. Our data indicate a mechanism in which tumor-infiltrating immune cells regulate tumor vessel phenotype.