title: Peripheral CD45RO, PD-1, and TLR4 expression in metastatic colorectal cancer patients treated with bevacizumab, fluorouracil, and irinotecan (FOLFIRI-B).
abstract: CD45RO, PD-1, and TLR4 immune pathways have proven pivotal in regulating antitumor response and correlate with survival for localized colorectal cancer (CRC). We evaluated if their peripheral expression was associated with outcome in metastatic CRC (mCRC). Thirty-one mCRC patients were eligible for this prospective study ( clinicaltrial.gov NCT01533740) and treated with first-line FOLFIRI-B. Blood was drawn before the first and third cycle and analyzed by flow cytometry for frequency (%) of CD4+, CD8+, CD45RO+, and PD1+ mononuclear cells and for TLR4 expression on neutrophils. Two cycles of chemotherapy determined changes in immune variables that were prognostically meaningful. Pre-third-cycle (ptc) CD45RO+CD8+cell% displayed a statistically significant association with progression-free survival (PFS) (median PFS 22.4 vs. 9.4 months for patients with CD45RO+CD8+cell%> vs. <the median value of 12%, respectively, p 0.02) and overall survival (OS) (2-year OS rate 62 vs. 44%, respectively, p 0.04). Surprisingly, ptc-PD1 overexpression was also associated with improved PFS of borderline statistical significance (HR 0.42, p 0.06). A Cox regression multivariate analysis for PFS including ptc-CD45RO+CD8+cell%, ptc-PD1+cell%, CEA, LDH, and Köhne risk class demonstrated CD45RO+CD8+cell% to be the only independent prognostic factor (HR 0.23, p 0.04). TLR4 and CD4 were not associated with the outcome. Peripheral CD8+CD45RO+ cells were confirmed to be of independent prognostic value in mCRC patients. Overexpression of the PD-1 immunosuppressor after two cycles of therapy may be a negative feedback mechanism, and therefore, an indirect sign of chemotherapy induced antitumor immune response with a favorable association with outcome. Enhancement of CD8+CD45RO+ cell response may be a fascinating therapeutic target to improve the efficacy of FOLFIRI-B.
authors.affiliation: Medical Oncology Unit, 'Tor Vergata' Clinical Center, University of Rome, Rome, Italy, v.formica1@gmail.com.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Formica
authors.forename: Vittore
authors.initials: V
authors.lastname: Cereda
authors.forename: Maria-Giovana
authors.initials: MG
authors.lastname: di Bari
authors.forename: Italia
authors.initials: I
authors.lastname: Grenga
authors.forename: Manfredi
authors.initials: M
authors.lastname: Tesauro
authors.forename: Palmirotta
authors.initials: P
authors.lastname: Raffaele
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferroni
authors.forename: Fiorella
authors.initials: F
authors.lastname: Guadagni
authors.forename: Mario
authors.initials: M
authors.lastname: Roselli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D017493:Leukocyte Common Antigens / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics*; D011446:Prospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000068258:Bevacizumab; D000077146:Irinotecan; D017493:Leukocyte Common Antigens; D005472:Fluorouracil; D002166:Camptothecin