TY - JOUR
T1 - Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells
AU - Jackaman, Connie
AU - Cornwall, S.M.J.
AU - Lew, A.M.
AU - Zhan, Y.
AU - Robinson, Bruce
AU - Nelson, Delia
PY - 2009
Y1 - 2009
N2 - The aim of the present study was to define the point at which mesothelioma T-cell responses fail in order to design better immunotherapies.A murine model of mesothelioma was used which was established with asbestos. Inoculation of tumour cells into syngeneic mice results in progressing tumours with similar histopathology to human mesothelioma. The tumour cells secrete a marker tumour antigen similar to secreted tumour-associated products, such as mesothelin.The mesothelioma microenvironment contains stromal elements including dendritic cells, effector CD8+ and CD4+ T-cells, and CD4+ T-regulatory (Tregs) cells, all of which are activated in situ, implying chronic inflammation. Tumour antigens are rapidly transported to draining lymph nodes wherein tumour-specific T-cell responses are generated. Despite the generation of potent CD8+ cytotoxic lymphocyte in lymphoid organs, those that infiltrate tumours cannot restrain tumour growth suggesting local suppression. Splenic Tregs did not suppress protective responses in adoptive transfer experiments suggesting that systemic Tregs play little role in regulating anti-mesothelioma immune responses. Finally, removal of CD25+ Tregs from the tumour site and lymphoid organs did not alter tumour growth with or without interleukin (IL)-2 or IL-21 immunotherapy.Tregs are not potent regulators of anti-mesothelioma immunity and targeting these cells may not improve results
AB - The aim of the present study was to define the point at which mesothelioma T-cell responses fail in order to design better immunotherapies.A murine model of mesothelioma was used which was established with asbestos. Inoculation of tumour cells into syngeneic mice results in progressing tumours with similar histopathology to human mesothelioma. The tumour cells secrete a marker tumour antigen similar to secreted tumour-associated products, such as mesothelin.The mesothelioma microenvironment contains stromal elements including dendritic cells, effector CD8+ and CD4+ T-cells, and CD4+ T-regulatory (Tregs) cells, all of which are activated in situ, implying chronic inflammation. Tumour antigens are rapidly transported to draining lymph nodes wherein tumour-specific T-cell responses are generated. Despite the generation of potent CD8+ cytotoxic lymphocyte in lymphoid organs, those that infiltrate tumours cannot restrain tumour growth suggesting local suppression. Splenic Tregs did not suppress protective responses in adoptive transfer experiments suggesting that systemic Tregs play little role in regulating anti-mesothelioma immune responses. Finally, removal of CD25+ Tregs from the tumour site and lymphoid organs did not alter tumour growth with or without interleukin (IL)-2 or IL-21 immunotherapy.Tregs are not potent regulators of anti-mesothelioma immunity and targeting these cells may not improve results
U2 - 10.1183/09031936.00101008
DO - 10.1183/09031936.00101008
M3 - Article
VL - 34
SP - 162
EP - 175
JO - The European Respiratory Journal
JF - The European Respiratory Journal
SN - 0903-1936
IS - 1
ER -