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Med Oncol (2013) 30:743DOI 10.1007/s12032-013-0743-0
ORIGINAL PAPER
Peripheral CD45RO, PD-1, and TLR4 expression in metastatic colorectal cancer patients treated with bevacizumab, uorouracil, and irinotecan (FOLFIRI-B)
Vincenzo Formica Vittore Cereda Maria-Giovana di Bari
Italia Grenga Manfredi Tesauro Palmirotta Raffaele
Patrizia Ferroni Fiorella Guadagni Mario Roselli
Received: 30 August 2013 / Accepted: 25 September 2013 / Published online: 11 October 2013 Springer Science+Business Media New York 2013
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 (http://clinicaltrial.gov
Web End =clinicaltrial. http://clinicaltrial.gov
Web End =gov NCT01533740) and treated with rst-line FOLFIRI-B. Blood was drawn before the rst and third cycle and analyzed by ow 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 signicant 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 signicance (HR 0.42, p 0.06). A Cox regression multivariate analysis for PFS including ptc-CD45RO?CD8?cell%, ptc-PD1?cell%, CEA, LDH, and Khne 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 conrmed 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 efcacy of FOLFIRI-B.
Keywords CD45RO PD-1 TLR4 Colorectal
cancer
Introduction
Metastatic colorectal cancer is the second leading cause of cancer death in developed countries [1, 2].
Although advances have been made in the last 15 years with the introduction of novel molecularly targeted...