Role of systemic inflammation and CD45RO+CD8+c cells in metastatic colorectal cancer

BACKGROUND: Systemic inflammation as measured by the inflammatory index Neutrophil/lymphocyte ratio(N/L) and activation of innate immunity pathways driven by TLR4 are negative prognostic factors for patients with localized colorectal cancer (CRC). Moreover, adaptive immunity pathways driven by CD45RO and PD-1 have proven pivotal in regulating antitumor response and correlate with survival for localized CRC. In the present study we evaluated if N/L and CD45RO, PD-1, and TLR4 peripheral expression was associated with outcome in metastatic CRC (mCRC) treated with standard first-line chemotherapy including bevacizumab, fluorouracil, and irinotecan (FOLFIRI-B). PATIENTS AND METHODS: mCRC patients eligible for this prospective study (clinicaltrial.gov NCT01533740) were 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. N/L was assessed before each treatment cycle. Innate and adaptive immune variables were correlated with outcome by Cox regression analysis, together with common clinical,biochemical and histological variables. RESULTS: Among 403 consecutive patients referred to our Unit between June 2008 and October 2011, 106 patients, 43 female and 63 male, were eligible for this trial and assessed for N/L; 31 patients had samples available for CD45RO, PD-1, and TLR4 expression analysis. At multivariate Cox regression analysis of all 106 enrolled patients, only N/L and CRP were confirmed to be independent prognostic factors, with N/L being the most powerful prognosticator (exp(b)=1.80,p 0.0019;mOS for patients with N/L< and >3.5= 41 v 12 months, respectively,p 0.01).Surprisingly, N/L changes during chemotherapy among patients with stable disease had an opposite effect on survival: patients with increasing or stable N/L had a 67% reduction in the risk of death as compared with patients with significant N/L decrease,p 0.02. Among the 31 patients assessable for adoptive immune variables, two cycles of chemotherapy determined changes 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