TY - JOUR
T1 - Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth
AU - Van Der Most, Robbert
AU - Currie, Andrew
AU - Cleaver, Amanda
AU - Salmons, Joanne
AU - Nowak, Anna
AU - Mahendran, Sathish
AU - Larma, I.
AU - Prosser, A.
AU - Robinson, Bruce
AU - Smyth, M.J.
AU - Scalzo, Tony
AU - Degli-Esposti, Mariapia
AU - Lake, Richard
PY - 2009
Y1 - 2009
N2 - Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinicalmodels clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immunesystem can be mobilized to generate anti-tumor immune responses in the context of chemotherapy.Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependenttumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in aCD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-a/b response and a profoundnegative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential forcurative responses. The important effector molecules used by the anti-tumor immune response included IFN-c and TRAIL.The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could becompensated by agonistic anti-TRAIL-receptor (DR5) antibodies.Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-,mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumorresolution and
AB - Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinicalmodels clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immunesystem can be mobilized to generate anti-tumor immune responses in the context of chemotherapy.Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependenttumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in aCD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-a/b response and a profoundnegative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential forcurative responses. The important effector molecules used by the anti-tumor immune response included IFN-c and TRAIL.The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could becompensated by agonistic anti-TRAIL-receptor (DR5) antibodies.Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-,mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumorresolution and
UR - http://www.scopus.com/inward/record.url?scp=70349170354&partnerID=8YFLogxK
UR - https://www.scopus.com/pages/publications/70349170354
U2 - 10.1371/journal.pone.0006982
DO - 10.1371/journal.pone.0006982
M3 - Article
C2 - 19746156
SN - 1932-6203
VL - 4
SP - Article number e6982, 11pp
JO - PLoS One
JF - PLoS One
IS - 9
ER -
