title: Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes.
abstract: Colorectal cancer is associated with chronic inflammation and immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Although chemotherapy reduces tumor burden at early stages, it tends to have limited effect on a progressive disease, possibly due to adverse effects on the immune system in dictating disease outcome. Here, we show that patients with advanced colorectal cancer display enhanced MDSC levels and reduced CD247 expression and that some conventional colorectal cancer chemotherapy supports the immunosuppressive tumor microenvironment. A FOLFOX combined therapy reduced immunosuppression, whereas a FOLFIRI combined therapy enhanced immunosuppression. Mechanistic studies in a colorectal cancer mouse model revealed that FOLFIRI-like therapy including the drugs CPT11 and 5-fluorouracil (5FU) damaged host immunocompetence in a manner that limits treatment outcomes. CPT11 blocked MDSC apoptosis and myeloid cell differentiation, increasing MDSC immunosuppressive features and mouse mortality. In contrast, 5FU promoted immune recovery and tumor regression. Thus, CPT11 exhibited detrimental immunoregulatory effects that offset 5FU benefits when administered in combination. Our results highlight the importance of developing therapeutic regimens that can target both the immune system and tumor towards improved personalized treatments for colorectal cancer.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Kanterman
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Sade-Feldman
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Biton
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Eliran
authors.initials: E
authors.lastname: Ish-Shalom
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lasry
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Aviya
authors.initials: A
authors.lastname: Goldshtein
authors.affiliation: Sharett Institute of Oncology, Hadassah University Medical Center Ein Kerem, Jerusalem, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Hubert
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel. michalb@ekmd.huji.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002454:Cell Differentiation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin