Multimarker assessment of B cell and plasma cell subsets and their prognostic role in the colorectal cancer microenvironment

Purpose: While the association between cytotoxic T lymphocytes and favorable prognosis in colorectal cancer is well established, the prognostic significance of B lymphocytes remain more ambiguous. This study aimed to assess the characteristics and significance of various B cell and plasma cell subsets in colorectal tumors. Experimental Design: We designed a seven-plex immunohistochemistry 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. Results: 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, multivariable HR for high (vs. low) plasma cell density was 0.48 (95% CI 0.32–0.72, Ptrend = 0.0005), while the corresponding HR in the validation cohort was 0.37 (95% CI 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 better prognosis. Conclusions: Plasma cell densities in the center of the tumor represent a relevant tumor immune biomarker in colorectal cancer, complementing the T cell density measurements.