Integrin β1 activation induces an anti-melanoma host response

• Published in: PloS one Vol. 12; no. 4; p. e0175300
• Main Authors: Ritsma, Laila, Dey-Guha, Ipsita, Talele, Nilesh, Sole, Xavier, Salony, Chowdhury, Joeeta, Ross, Kenneth N, Ramaswamy, Sridhar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2017; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Animals; Antibodies - immunology; Antigens; Apoptosis; Biology and Life Sciences; Cancer; CD8 antigen; Cell activation; Cell cycle; Cell growth; Cell Line, Tumor; Cell migration; Cell Proliferation; Cell surface; Cell survival; Cell Transformation, Neoplastic; Chemotherapy; Clinical trials; Correlation; Extracellular matrix; Extracellular Space - metabolism; Female; Fibroblasts; Immune checkpoint; Integrin beta1 - immunology; Integrin beta1 - metabolism; Kinases; Leukocyte migration; Lymphocytes; Lymphocytes T; Markers; Medical schools; Medicine and Health Sciences; Melanoma; Melanoma - blood supply; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Metastasis; Mice; Mice, Nude; Mutation; Neovascularization, Pathologic - immunology; Proteins; Research and Analysis Methods; Signal Transduction - immunology; Survival; Survival Analysis; T cell receptors; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Transcription; Transforming Growth Factor beta - metabolism; Transforming growth factor-b1; Tumor Microenvironment - immunology; Tumor suppression; Tumor-infiltrating lymphocytes; Tumors; Xenografts; United States > US; Netherlands; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0175300

TGF-β is a cytokine thought to function as a tumor promoter in advanced malignancies. In this setting, TGF-β increases cancer cell proliferation, survival, and migration, and orchestrates complex, pro-tumorigenic changes in the tumor microenvironment. Here, we find that in melanoma, integrin β1-mediated TGF-β activation may also produce tumor suppression via an altered host response. In the A375 human melanoma cell nu/nu xenograft model, we demonstrate that cell surface integrin β1-activation increases TGF-β activity, resulting in stromal activation, neo-angiogenesis and, unexpectedly for this nude mouse model, increase in the number of intra-tumoral CD8+ T lymphocytes within the tumor microenvironment. This is associated with attenuation of tumor growth and long-term survival benefit. Correspondingly, in human melanomas, TGF-β1 correlates with integrin β1/TGF-β1 activation and the expression of markers for vasculature and stromal activation. Surprisingly, this integrin β1/TGF-β1 transcriptional footprint also correlates with the expression of markers for tumor-infiltrating lymphocytes, multiple immune checkpoints and regulatory pathways, and, importantly, better long-term survival of patients. These correlations are unique to melanoma, in that we do not observe similar associations between β1 integrin/TGF-β1 activation and better long-term survival in other human tumor types. These results suggest that activation of TGF-β1 in melanoma may be associated with the generation of an anti-tumor host response that warrants further study.