Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy
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nihms752883.pdf
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2.95 MB
Format
Adobe PDF
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Author(s)
Pfirschke, Christina
Engblom, Camilla
Rickelt, Steffen
Cortez-Retamozo, Virna
Garris, Christopher
Pucci, Ferdinando
Yamazaki, Takahiro
Poirier-Colame, Vichnou
Newton, Andita
Redouane, Younes
Date Issued
February 2016
Journal
Immunity
Publisher
Elsevier BV
Citation
Pfirschke, Christina et al. “Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy.” Immunity 44, 2 (February 2016): 343–354 © 2016 Elsevier Inc
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.IMMUNI.2015.11.024
