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Intratumoral CD3+ and Nkp46+ Cells Protect Against Tumor Progression in Resected Colorectal Liver Metastases Treated With Neoadjuvant Chemotherapy
Matteo Maria Cimino*1, Matteo Donadon1, Kelly Hudspeth2, Luca Di Tommaso3, Max Preti2, Massimo Roncalli3, Domenico Mavilio2, Guido Torzilli1
1Department of Surgery Division of Hepatobiliary & General Surgery, Humanitas Research Hospital & Humanitas University, Rozzano, MI, Italy; 2Unit of Clinical and Experimental Immunology, Humanitas Research Hospital & Humanitas University, Rozzano, Italy; 3Department of Pathology, Humanitas Research Hospital & Humanitas University, Rozzano, Italy
Background. Chemotheraphy (CHT) response is one of the most important prognostic factor in the oncosurgical approach to colorectal liver metastases CRLM. Several tumoral and non-tumoral factors, such as the innate immune system (IIS) may play an important role in chemosensitivity. The aim of this study was to investigate the role of the IIS in a setting of patient affected by CRLM treated with neoadjuvant CHT and liver resection considering pathological features and oncological long-term outcome.
Methods: In 121 patients undergoing liver resection for CRLM. between 2005 and 2013 preoperatively treated with standard CHT with or without biological agents we tested immunoreactivity to CD3+ and NKp46+ cells inside the tumor, at the border between the tumor and the normal liver, and inside the normal liver with computer-assisted image analyses. The relationship between IIS, chemotherapy response rate, and long-term survival were investigated.
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 immunoreactivity to CD3+ and NKp46+ cells seems to play an important role in CHT response rate. Increased intratumoral density of IIS cells seems to improve overall Survival. Some chemotherapy regimens may be more effective to enhance intratumoral CD3+ an NKp46+ migration. Further external validations are required to confirm our promising findings.
Survival by intratumoral CD3+ and NK cells density.
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