Ritsma, LailaDey-Guha, IpsitaTalele, NileshSole, XavierSalonyChowdhury, JoeetaRoss, KennethRamaswamy, Sridhar2017-06-152017Ritsma, Laila, Ipsita Dey-Guha, Nilesh Talele, Xavier Sole, SalonyJoeeta Chowdhury, Kenneth N. Ross, and Sridhar Ramaswamy. 2017. “Integrin β1 activation induces an anti-melanoma host response.” PLoS ONE 12 (4): e0175300. doi:10.1371/journal.pone.0175300. http://dx.doi.org/10.1371/journal.pone.0175300.http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029849TGF-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.en-USBiology and Life SciencesCell BiologyCell AdhesionIntegrinsCellular Structures and OrganellesExtracellular MatrixMedicine and Health SciencesOncologyCancer TreatmentCellular TypesAnimal CellsBlood CellsWhite Blood CellsT CellsImmune CellsImmunologyBiology and life sciencesCell biologySignal transductionCell signalingSignaling cascadesTGF-beta signaling cascadeCancers and NeoplasmsMelanomasHistochemistry and Cytochemistry TechniquesImmunohistochemistry TechniquesImmunologic TechniquesExperimental Organism SystemsModel OrganismsMouse ModelsAnimal ModelsCellular typesAnimal cellsBlood cellsWhite blood cellsT cellsCytotoxic T cellsImmune cellsMedicine and health sciencesJournal Article2017-06-1510.1371/journal.pone.0175300