CD226 has been reported to participate in the rescue of CD8^(+)T cell dysfunction.In this study,we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes(TILs)derived from colorectal cancer(CRC...CD226 has been reported to participate in the rescue of CD8^(+)T cell dysfunction.In this study,we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes(TILs)derived from colorectal cancer(CRC)liver metastases treated with chemotherapy and radical surgery.TILs from 43 metastases were isolated and analyzed ex vivo usingflow cytometry.CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry.Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets.CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors.CD226 on CD8^(+)T cells was not specifically coexpressed with other immune checkpoints,such as PD1,TIGIT,and TIM3,in liver metastases.Multivariate Cox regression analysis revealed CD226 expression on CD8^(+)T cells to be an independent prognostic factor(p=0.003),along with CD3 density at invasion margins(p=0.003)and TIGIT expression on CD4^(+)T cells(p=0.019).CD155 was not associated with the prognostic value of CD226.Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors.Downregulation of CD226 on CD8^(+)TILs in the liver microenvironment was restored by IL15 treatment.Overall,CD226 expression on liver metastasis-infiltrating CD8^(+)T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.展开更多
Complete resection stands as the only potentially curative treatment.Being often late diagnosed,vascular and biliary structures are frequently involved owing to centrally located and/or large lesions at the time of di...Complete resection stands as the only potentially curative treatment.Being often late diagnosed,vascular and biliary structures are frequently involved owing to centrally located and/or large lesions at the time of diagnosis.Consequently,complete resection can require complex hepatectomy often on diseased liver,associated with important risks of mortality and morbidity while benefits in terms of prolonged survival remain often uncertain.To date,only one large series investigating actual long-term survival after curative-intent hepatectomy reported an actual 5-year OS of 13%(1).Indeed,around two thirds of patients experience recurrence,mostly to the liver,and eventually die of disease recurrence(2).These observations suggest first that patient selection for resection might be inadequate.Second,surgery alone seems not able to provide sufficient disease control.For instance,recurrence is frequently observed even with early tumours classified AJCC 8th Edition stage IA disease resulting in an estimated 5-year disease specific survival nearing 60%only.展开更多
文摘CD226 has been reported to participate in the rescue of CD8^(+)T cell dysfunction.In this study,we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes(TILs)derived from colorectal cancer(CRC)liver metastases treated with chemotherapy and radical surgery.TILs from 43 metastases were isolated and analyzed ex vivo usingflow cytometry.CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry.Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets.CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors.CD226 on CD8^(+)T cells was not specifically coexpressed with other immune checkpoints,such as PD1,TIGIT,and TIM3,in liver metastases.Multivariate Cox regression analysis revealed CD226 expression on CD8^(+)T cells to be an independent prognostic factor(p=0.003),along with CD3 density at invasion margins(p=0.003)and TIGIT expression on CD4^(+)T cells(p=0.019).CD155 was not associated with the prognostic value of CD226.Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors.Downregulation of CD226 on CD8^(+)TILs in the liver microenvironment was restored by IL15 treatment.Overall,CD226 expression on liver metastasis-infiltrating CD8^(+)T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.
基金The authors acknowledge the Association Francaise de Chirurgie(AFC-IHCC study group).
文摘Complete resection stands as the only potentially curative treatment.Being often late diagnosed,vascular and biliary structures are frequently involved owing to centrally located and/or large lesions at the time of diagnosis.Consequently,complete resection can require complex hepatectomy often on diseased liver,associated with important risks of mortality and morbidity while benefits in terms of prolonged survival remain often uncertain.To date,only one large series investigating actual long-term survival after curative-intent hepatectomy reported an actual 5-year OS of 13%(1).Indeed,around two thirds of patients experience recurrence,mostly to the liver,and eventually die of disease recurrence(2).These observations suggest first that patient selection for resection might be inadequate.Second,surgery alone seems not able to provide sufficient disease control.For instance,recurrence is frequently observed even with early tumours classified AJCC 8th Edition stage IA disease resulting in an estimated 5-year disease specific survival nearing 60%only.
