title: Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy.
abstract: Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL. This effect was mediated by transient but dramatic upregulation of the mannose-6-phosphate receptor (MPR) on the tumor cell surface. Antitumor effects of combined treatment related to the kinetics of MPR upregulation and abrogation of this event abolished the combined effect of immunotherapy and chemotherapy. MPR accumulation on the tumor cell surface during chemotherapy was observed in different mouse tumor models and in patients with multiple myeloma. Notably, this effect was the result of redistribution of the receptor caused by chemotherapy-inducible autophagy. Together, our findings reveal one molecular mechanism through which the antitumor effects of conventional cancer chemotherapy and immunotherapy are realized.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
authors.forename: Rupal
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Chun
authors.initials: C
authors.lastname: Huang
authors.forename: Hyun-Il
authors.initials: HI
authors.lastname: Cho
authors.forename: Mark
authors.initials: M
authors.lastname: Lloyd
authors.forename: Joseph
authors.initials: J
authors.lastname: Johnson
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weber
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D004358:Drug Therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D060888:Real-Time Polymerase Chain Reaction; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D017527:Receptor, IGF Type 2