Integrin ?1 activation induces an anti-melanoma host response.

ABSTRACT: TGF-? is a cytokine thought to function as a tumor promoter in advanced malignancies. In this setting, TGF-? increases cancer cell proliferation, survival, and migration, and orchestrates complex, pro-tumorigenic changes in the tumor microenvironment. Here, we find that in melanoma, integrin ?1-mediated TGF-? 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 ?1-activation increases TGF-? 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-?1 correlates with integrin ?1/TGF-?1 activation and the expression of markers for vasculature and stromal activation. Surprisingly, this integrin ?1/TGF-?1 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 ?1 integrin/TGF-?1 activation and better long-term survival in other human tumor types. These results suggest that activation of TGF-?1 in melanoma may be associated with the generation of an anti-tumor host response that warrants further study.

SUBMITTER: Ritsma L 

PROVIDER: S-EPMC5407755 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature