CD8+ T-cell primary tumor infiltration is associated with improved colorectal cancer (CRC) outcome. However, the interaction between CD8+ T-cell infiltration and intra-tumor PD-L1 expression has not been previously characterized. This study aims to explore the impact of PD-L1 expression and degree of CD8+ T-cell infiltration on the outcome of patients with stage II and III CRC.
CD8, PD-1, PD-L1, cytokeratin 20, and CD68 expression were quantified via multi-spectral immunohistochemistry of primary CRC tumors from 35 patients with recurrent disease (cases) and 36 patients without recurrence (controls). The TCGA (The Cancer Genome Atlas) and the NCBI-GEO (Gene Expression Omnibus) datasets of 385 and 828 stage II-III cases, respectively, were used to validate the prognostic value of the discovery set biomarkers, both for relapse free survival (RFS) and overall survival (OS).
In the 71-patient discovery case-control set, densities of CD8+ and PD-L1+ cells in tumor microenvironment classified patients into three distinct populations. High CD8+ cell infiltration (above median) and high PD-L1 expression (>90 percentile) was associated with high risk of relapse: all 7/7 patients with CD8Hi/PD-L1Hi experienced disease relapse, despite being enriched in mismatch repair deficiency (4 patients). Low CD8+ cell infiltration was associated with a high relapse rate irrespective of PD-L1 status: 80% of patients with CD8L relapsed. CD8Hi in the absence of high PD-L1 expression (CD8Hi/PD-L1L) had the lowest risk of relapse: 7% of patients relapsed. The validation data sets confirmed that the CD8Hi/PD-L1L and the CD8L groups carried an inferior RFS (NCBI-GEO data set: HR = 1.655, p = 0.02) and OS (TCGA data set: HR = 3.556, p = 0.0095) in comparison to the CD8Hi/PD-L1L group. A multivariate analysis that includes age, stage, and mismatch repair (MMR) status, confirmed the independent impact of both CD8Hi and PD-L1Hi on RFS and OS in both validation sets.
CD8Hi/PD-L1Hi defines 10% of patients with stage II/III CRC and confers a high risk of relapse, despite enrichment with MMR deficiency. This subgroup of patients may be suitable for the investigation of PD-1 checkpoint inhibitors.
Clinical trial identification
Legal entity responsible for the study
City of Hope
All authors have declared no conflicts of interest.