TGF-beta is a cytokine thought to function as a tumor promoter in advanced malignancies. In this setting, TGF-beta increases cancer cell proliferation, survival, and migration, and orchestrates complex, pro-tumorigenic changes in the tumor microenvironment. Here, we find that in melanoma, integrin beta1-mediated TGF-beta 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 beta1-activation increases TGF-beta 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-beta1 correlates with integrin beta1/TGF-beta1 activation and the expression of markers for vasculature and stromal activation. Surprisingly, this integrin beta1/TGF-beta1 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 beta1 integrin/TGF-beta1 activation and better long-term survival in other human tumor types. These results suggest that activation of TGF-beta1 in melanoma may be associated with the generation of an anti-tumor host response that warrants further study.

Author Info: (1) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (2) Cancer Center, Massachuse

Author Info: (1) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (2) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (3) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (4) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (5) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (6) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. (7) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. (8) Cancer Center, Massachusetts General Hospital, Boston, MA, United States of America. Harvard Medical School, Boston, MA, United States of America. Broad Institute of Harvard & MIT, Cambridge, MA, United States of America. Harvard Stem Cell Institute, Cambridge, MA, United States of America. Harvard-Ludwig Center for Cancer Research, Cambridge, MA, United States of America.