Transforming growth factor-β1 immobilises dendritic cells within skin tumours and facilitates tumour escape from the immune system

Abstract

Human skin tumours often regress spontaneously due to immune rejection. Murine skin tumours model this behaviour; some regress and others progress in syngeneic immunocompetent hosts. Previous studies have shown that progressor but not regressor skin tumours inhibit dendritic cell (DC) migration from the tumour to draining lymph nodes, and transforming growth factor-beta1 (TGF-beta1) has been identified as a responsible factor. To determine whether increased production of TGF-beta1 in the absence of other differences inhibits DC migration from the tumour and enables it to evade immune destruction, a murine regressor squamous cell carcinoma clone was transfected with the gene for TGF-beta1. This enhanced growth in vitro and in vivo, causing it to become a progressor. TGF-beta1 transfection reduced the number of infiltrating DCs by about 25%. Quantitation of CD11c+ E-cadherin+ (epidermally derived) DCs in lymph nodes determined that TGF-beta1 reduced the number of DCs that migrated from the tumour to undetectable levels. This was supported by showing that TGF-beta1 reduced DC migration from cultured tumour explants by greater than tenfold. TGF-beta1 transfection also reduced the number of infiltrating CD4 and CD8 T cells. Thus, TGF-beta1 production by skin tumours is sufficient to immobilise DCs within the tumour, preventing their migration to lymph nodes. This reduces the number of T cells that infiltrate the tumour, preventing regression. Thus, TGF-beta1 is a key regulator of whether skin tumours regress or progress.

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Exposure of pDCs to TGF-β prevents type I interferon secretion in response to TLR7/9 ligands, while in contrast, the consequences of TGF-β on the antigenpresenting cell capacities of pDC are less clear, since TGF-β-exposed pDCs may lead to both regulatory T cell and interleukin-17-secreting cell polarization [44]. In addition, TGF-β decreases cDCs migration and increases apoptosis, which decreases antigen presentation and dampens the adaptive immune response [45,46].…”

TGFβ-dependent gene expression profile during maturation of dendritic cells

“…13 It was also demonstrated that tumors evade the host immune attack by secreting TGFb, which inhibits DC migration to the draining LN and thereby preventing the presentation of tumor antigens to T cells. 14,15 To gain insights into the molecular mechanism underlying the inhibitory effect of TGFb on maturation and function of DC, we characterized the effect of TGFb on global gene expression of DC, when cells were driven to maturation by exposure to LPS.…”

Comparação das contagens das células de Langerhans de tecidos contendo carcinoma anal em doentes com e sem infecção pelo HIV

“…De fato, a produção de TGF-beta-1 por tumores de pele é suficiente para imobilização das LC, impedindo sua migração para os linfonodos, reduzindo o nú-mero de células T que infiltrariam o tumor, evitando sua regressão. 27 Nossa casuística revelou que os doentes HIV-positivos com pior evolução tinham as menores contagens séricas de linfócitos T CD4+. Revisando a literatura, observamos que a presença dessas células abaixo de 100/mm³ e a carga viral HIV elevada, que sugerem tratamento ineficaz ou ausente e denotam imunodepressão, são fatores de risco para o aparecimento do câncer.…”

“…Sabe-se também que a incidência desses tumores é maior em doentes imunodeprimidos, nos quais os linfócitos T CD4+ estão diminuídos. 27 Com objetivo de conhecer as diferenças entre os carcinomas anais em situações de imunocompetência e imunodepressão, comparamos as contagens de LC no tecido tumoral de doentes com e sem AIDS.…”