Multimarker Assessment of B-Cell and Plasma Cell Subsets and Their Prognostic Role in the Colorectal Cancer Microenvironment.

Abstract

Although the association between cytotoxic T lymphocytes and favorable prognosis in colorectal cancer is well established, the prognostic significance of B lymphocytes remains more ambiguous. This study aimed to assess the characteristics and significance of various B-cell and plasma cell subsets in colorectal tumors. We designed a seven-plex IHC assay, combined with machine learning-based image analysis, to identify various B-cell and plasma cell populations and applied it to study a cohort of 912 colorectal tumors. We assessed the prognostic significance of B-cell and plasma cell densities using Kaplan-Meier estimators and Cox regression models. Additionally, we designed a more clinically applicable three-plex assay, which we used to study B-cell and plasma cell densities in a separate validation cohort of 737 patients. High plasma cell density in the center of the tumor was associated with longer cancer-specific survival independent of disease stage, mismatch repair status, T-cell densities, and other covariates. In the study cohort, the multivariable HR for high (vs. low) plasma cell density was 0.48 (95% confidence interval, 0.32-0.72; Ptrend = 0.0005), whereas the corresponding HR in the validation cohort was 0.37 (95% confidence interval, 0.21-0.65; Ptrend = 0.0003). Of the specific subsets, IgG1-IgG2- plasma cells showed the strongest association with improved survival. High B-cell densities were not independently associated with a better prognosis. Plasma cell densities in the center of the tumor represent a relevant tumor-immune biomarker in colorectal cancer, complementing T-cell density measurements.