Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy

Christina Pfirschke, Camilla Engblom, Steffen Rickelt, Virna Cortez-Retamozo, Christopher Garris, Ferdinando Pucci, Takahiro Yamazaki, Vichnou Poirier-Colame, Andita Newton, Younes Redouane, Yi Jang Lin, Gregory Wojtkiewicz, Yoshiko Iwamoto, Mari Mino-Kenudson, Tiffany G. Huynh, Richard O. Hynes, Gordon J. Freeman, Guido Kroemer, Laurence Zitvogel, Ralph WeisslederMikael J. Pittet

Research output: Contribution to journalArticle

260 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)343-354
Number of pages12
JournalImmunity
Volume44
Issue number2
DOIs
StatePublished - Feb 16 2016
Externally publishedYes

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Drug Therapy
Neoplasms
T-Lymphocytes
oxaliplatin
Therapeutics
Immunity
Pharmaceutical Preparations
Toll-Like Receptor 4
Genetic Models
Immunotherapy
Cyclophosphamide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Pfirschke, C., Engblom, C., Rickelt, S., Cortez-Retamozo, V., Garris, C., Pucci, F., ... Pittet, M. J. (2016). Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity, 44(2), 343-354. https://doi.org/10.1016/j.immuni.2015.11.024

Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. / Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen; Cortez-Retamozo, Virna; Garris, Christopher; Pucci, Ferdinando; Yamazaki, Takahiro; Poirier-Colame, Vichnou; Newton, Andita; Redouane, Younes; Lin, Yi Jang; Wojtkiewicz, Gregory; Iwamoto, Yoshiko; Mino-Kenudson, Mari; Huynh, Tiffany G.; Hynes, Richard O.; Freeman, Gordon J.; Kroemer, Guido; Zitvogel, Laurence; Weissleder, Ralph; Pittet, Mikael J.

In: Immunity, Vol. 44, No. 2, 16.02.2016, p. 343-354.

Research output: Contribution to journalArticle

Pfirschke, C, Engblom, C, Rickelt, S, Cortez-Retamozo, V, Garris, C, Pucci, F, Yamazaki, T, Poirier-Colame, V, Newton, A, Redouane, Y, Lin, YJ, Wojtkiewicz, G, Iwamoto, Y, Mino-Kenudson, M, Huynh, TG, Hynes, RO, Freeman, GJ, Kroemer, G, Zitvogel, L, Weissleder, R & Pittet, MJ 2016, 'Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy', Immunity, vol. 44, no. 2, pp. 343-354. https://doi.org/10.1016/j.immuni.2015.11.024
Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F et al. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity. 2016 Feb 16;44(2):343-354. https://doi.org/10.1016/j.immuni.2015.11.024
Pfirschke, Christina ; Engblom, Camilla ; Rickelt, Steffen ; Cortez-Retamozo, Virna ; Garris, Christopher ; Pucci, Ferdinando ; Yamazaki, Takahiro ; Poirier-Colame, Vichnou ; Newton, Andita ; Redouane, Younes ; Lin, Yi Jang ; Wojtkiewicz, Gregory ; Iwamoto, Yoshiko ; Mino-Kenudson, Mari ; Huynh, Tiffany G. ; Hynes, Richard O. ; Freeman, Gordon J. ; Kroemer, Guido ; Zitvogel, Laurence ; Weissleder, Ralph ; Pittet, Mikael J. / Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. In: Immunity. 2016 ; Vol. 44, No. 2. pp. 343-354.
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