Effect of intratumoral CD3+ and NKp46+ cells on tumor progression in resected colorectal liver metastases treated with neoadjuvant chemotherapy.

Abstract

281 Background: The long-term outcome of patients resected for colorectal liver metastases (CLM) after neoadjuvant chemotherapy (CHT) depends by several tumoral and non-tumoral factors, such as the immune response to the tumor and to the CHT. The aim of this study was to investigate the impact of the pathological and immunological response in patients undergoing liver resection for CLM after CHT in regards to the long-term outcome. Methods: The immunoreactivity to CD3+ and NKp46+ cells inside the tumor, at the border between the tumor and the normal liver, and inside the normal liver was tested by computer-assisted image analyses in 121 patients undergoing liver resection for CLM between 2005 and 2013 preoperatively treated with oxaliplatin or irinotecan with or without bevacizumab or cetuximab. The survival was assessed in relation to several prognostic factors and to that immunoreactivity. Results: At univariate analysis T1/T2- and N0-status of the primary tumor, metachronous CLM, the radiological response, and the higher density of intratumoral CD3+ ( > 1%) and of NKp46+ (mean > 1) were found to be significantly associated with prolonged survival, but only intratumoral CD3+ ( > 1%) and NKp46+ (mean > 1) were significant on multivariate analysis (P = 0.005 and P = 0.004 respectively). On logistic regression analysis the metachronous CLM (OR = 2.781; P = 0.002), the use of irinotecan and cetuximab (OR = 3.891; P = 0.001) and the radiological response (OR = 3.219; P = 0.001) were found to be associated with increasing density of intratumoral CD3+ and NKp46+ cells. No significant associations were found with CLM number or size, CEA, or number of CHT courses. Combining the intratumoral CD3+ and NKp46+ cells density we defined four stages of survival (P = 0.003): patients presenting intratumoral CD3+ ( > 1%) and NKp46+ (mean > 1) had 100% overall survival at 5 years. Conclusions: Intratumoral CD3+ and NKp46+ cells density is a crucial prognostic factor in patients undergoing hepatic resection for CLM after CHT, and the kind of CHT seems related to their density. Further external validations are required to confirm our promising findings.