Abstract
BackgroundColorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females. PD-1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment. However, the prognostic value of PD-1/PD-L1 in CRC remains unclear.MethodsThe Cancer Genome Atlas (TCGA) database (N = 356) and Fudan University Shanghai Cancer Center (FUSCC) cohort of patients (N = 276) were adopted to analyze the prognostic value of PD-L1 in colorectal tumor cells (TCs) and of PD-1 in tumor infiltrating cells (TILs) for CRC. Subgroup analyses were conducted in FUSCC cohort according to patients’ status of mismatch repair.ResultsIn TCGA cohort, the cut-off values of PD-1 and PD-L1 expression were determined by X-tile program, which were 4.40 and 2.92, respectively. Kaplan-Meier analysis indicated that higher PD-1 and PD-L1 expressions correlated with better OS (P = 0.032 and P = 0.002, respectively). In FUSCC cohort, expressions of PD-1 on TILs and PD-L1 on TCs were analyzed separately by immunohistochemistry (IHC) staining based on a TMA sample (N = 276) and revealed that both TILs-PD-1 and TCs-PD-L1 were associated with OS (P = 0.006 and P = 0.002, respectively) and DFS (P = 0.025 and P = 0.004, respectively) of CRC patients. Multivariate Cox regression analysis indicated TILs-PD-1 was an independent prognostic factor both for OS and DFS of CRC patients (P < 0.05). Subgroup analyses showed that TILs-PD-1 was an independent prognostic factor for both OS and DFS in CRC patients in MSS-proficient subgroup (P < 0.05), while neither of them correlated with OS or DFS in MSS-deficient subgroup (P > 0.05).ConclusionsHigher expressions of PD-1 and PD-L1 correlates with better prognosis of CRC patients. TILs-PD-1 is an independent prognostic factor for OS and DFS of CRC patients, especially for MMR-proficient subgroup.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0539-x) contains supplementary material, which is available to authorized users.
Highlights
Colorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females
Tissue microarray (TMA) construction and clinicopathological features The tissue microarray (TMA) used for this study includes 276 unselected, non-consecutive, primary, and sporadic CRCs treated between January 2007 and November 2009 in Fudan University Shanghai Cancer Center (FUSCC)
As this study described the prognosis of patients with CRC, analysis of overall survival (OS) and DFS were ascertained
Summary
Colorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females. PD-1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, accounting for approximately 9.7 % of total cancer cases and approximately 8.5 % of cancer deaths [1]. Evidence has shown that tumor infiltration by activated CD8+ cytotoxic T lymphocytes correlates with better survival of CRC patients [4]. PD1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment, and is a negative feedback system that represses Th1 cytotoxic immune responses [5]. Compared to PD-L2, which can be detected only in activated dendritic cells (DC) and macrophages, PD-L1 is constitutively expressed by T and B cells, DC and macrophages [7, 8], and it is expressed in additional cell types, such as endothelial, pancreatic and muscle cells [9]
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