title: Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy.
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.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Pfirschke
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Engblom
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rickelt
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Virna
authors.initials: V
authors.lastname: Cortez-Retamozo
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Garris
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.affiliation: Gustave Roussy Cancer Campus, 94805 Villejuif, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Gustave Roussy Cancer Campus, 94805 Villejuif, France.
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andita
authors.initials: A
authors.lastname: Newton
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Younes
authors.initials: Y
authors.lastname: Redouane
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yi-Jang
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wojtkiewicz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Tiffany G
authors.initials: TG
authors.lastname: Huynh
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Gustave Roussy Cancer Campus, 94805 Villejuif, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Gustave Roussy Cancer Campus, 94805 Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA. Electronic address: mpittet@mgh.harvard.edu.
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D045744:Cell Line, Tumor; D059333:Central Nervous System Sensitization / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D004358:Drug Therapy / Q000379:methods; D018816:Genes, cdc / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D009944:Organoplatinum Compounds; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000077150:Oxaliplatin; D003520:Cyclophosphamide