In an analysis reported by Frei et al in The Lancet Oncology, multiplex immunofluorescence staining of tissue microarrays of samples from patients with stage II to III colorectal cancer showed that densities of CD8-positive and Foxp3-positive cells were associated with recurrence-free interval.
As stated by the investigators, “Tumor-infiltrating CD8-positive cytotoxic T cells confer favorable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear, and so we sought to investigate their prognostic value in two large clinical trial cohorts.”
Study Details
Multiplex immunofluorescence staining of tissue microarrays was used to assess densities of CD8-, CD20-, Foxp3-, and CD68-positive cells in the intraepithelial and intrastromal compartments from tumor samples of patients with stage II to III colorectal cancer from the SCOT trial and the QUASAR 2 trial. The SCOT trial assessed 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy; the QUASAR 2 trial compared adjuvant capecitabine with or without bevacizumab. The SCOT cohort was used for discovery and the QUASAR 2 cohort was used for validation.
Key Findings
The study included 2,340 cases from the SCOT trial and 1,069 from the QUASAR 2 trial.
Univariate analysis in cases from the SCOT cohort showed strong prognostic value for recurrence-free interval for intraepithelial CD8 (CD8-IE) as a continuous variable (hazard ratio [HR] for the 75th vs 25th percentile = 0.73, P = 2.5 × 10-16), intrastromal FoxP3 (FoxP3-IS; HR for the 75th vs 25th percentile = 0.71, P = 1.5 × 10-¹³), and intraepithelial FoxP3 (FOXP3-IE; HR for the 75th vs 25th percentile = 0.89, P = 1.5 × 10-⁴). Other markers showed weak or no associations with recurrence-free interval.
On multivariate analysis, CD8-IE (HR for the 75th vs 25th percentile = 0.79, P = 8.7 × 10-⁸) and FoxP3-IS (HR for the 75th vs 25th percentile = 0.80, P = 1.5 × 10-⁵) were independent markers for recurrence-free survival. A composite marker of CD8-IE and FoxP3-IS was superior to either marker alone when assessed as a continuous variable (adjusted HR for the 75th vs 25th percentile = 0.70, P = 5.1 × 10-¹¹) and when categorized into low-, intermediate-, and high-density groups using previously reported cutpoints (adjusted HR for intermediate vs high = 1.68, P = 1.3 × 10-⁴, and for low vs high = 2.58, P = 7.9 × 10-¹⁰).
In the QUASAR 2 cohort, the prognostic value of the composite marker of CD8-IE plus FoxP3-IS was confirmed both as a continuous variable (adjusted HR for the 75th vs 25th percentile = 0.84, P = .012) and as a categorical variable for low vs high density (adjusted HR = 1.80, P = .0071) but not for intermediate vs high density (adjusted HR = 1.30, P = .17).
The investigators concluded, “Combined evaluation of [CD8-IE and FoxP3-IS] could help to refine risk stratification in colorectal cancer. Investigation of [FoxP3-IS] cells as an immunotherapy target in colorectal cancer might be merited.”
David N. Church, DPhil, of the Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation. For full disclosures of the study authors, visit thelancet.com.
