Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy
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Author
Pfirschke, Christina
Engblom, Camilla
Rickelt, Steffen
Cortez-Retamozo, Virna
Garris, Christopher
Pucci, Ferdinando
Yamazaki, Takahiro
Colame, Vichnou Poirier
Newton, Andita
Redouane, Younes
Lin, Yi-Jang
Wojtkiewicz, Gregory
Iwamoto, Yoshiko
Mino-Kenudson, Mari
Huynh, Tiffany
Hynes, Richard
Freeman, Gordon
Kroemer, Guido
Zitvogel, Laurence
Weissleder, Ralph
Pittet, Mikael
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https://doi.org/10.1016/j.immuni.2015.11.024Metadata
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Pfirschke, Christina, Camilla Engblom, Steffen Rickelt, Virna Cortez-Retamozo, Christopher Garris, Ferdinando Pucci, Takahiro Yamazaki, et al. 2016. “Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy.” Immunity 44 (2): 343–54. https://doi.org/10.1016/j.immuni.2015.11.024.Abstract
Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.Terms of Use
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:41384245
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