ABSTRACT
Melanoma is the deadliest form of skin cancer with rising incidence, creating a significant health problem. We discovered increased expression of bone morphogenetic protein 6 (BMP6) in melanoma cells and tissues, and observed that BMP6 deficiency caused significantly delayed tumor onset and decelerated tumor progression in a melanoma mouse model. Moreover, we determined that BMP6 inhibits dermal mast cell recruitment and found that mast cell-derived mediators significantly reduced melanoma growth in vitro. In line with this, mast cell deficiency accelerated tumor onset and progression in a melanoma mouse model. Analysis of human melanoma tissues revealed a strong negative correlation between melanoma proliferation and mast cell infiltration. This study elucidates a novel role of BMP6-induced modulation of the tumor microenvironment.
Subject(s)
Bone Morphogenetic Protein 6/metabolism , Melanoma/metabolism , Neoplasm Proteins/metabolism , Neoplasms, Experimental/metabolism , Skin Neoplasms/metabolism , Tumor Microenvironment , Animals , Bone Morphogenetic Protein 6/genetics , Cell Line, Tumor , Female , Humans , Male , Melanoma/genetics , Melanoma/pathology , Mice , Mice, Transgenic , Neoplasm Proteins/genetics , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathologyABSTRACT
The immune system in sepsis is impaired as seen by reduced numbers and function of immune cells and impaired antigen-specific antibody responses. We studied T cell function in septic mice using cecal ligation and puncture (CLP) as a clinically relevant mouse model for sepsis. The proliferative response of CD4(+) and CD8(+) T cells was suppressed in septic mice. Adoptive transfer experiments demonstrated that the T cells were not intrinsically altered by CLP. Instead, the septic host environment was responsible for this T cell suppression. While CLP-induced suppression was dependent on TNF activity, neither the activation of TNF receptors type 1 nor TNF receptor type 2 alone was sufficient to generate sepsis-induced suppression showing that the two TNF receptors can substitute each other. Specific depletion of regulatory T (Treg) cells improved the impaired T cell proliferation in septic recipients demonstrating participation of Treg in sepsis-induced suppression. In summary, sepsis leads to TNF-dependent suppression of T cell proliferation in vivo involving induction of Treg cells.
