In Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Focal T lymphocyte aggregates commonly occur in colorectal cancer; however, their biological significance is unknown. To study focal aggregates of T lymphocytes, a deep learning-based framework for automated identification of T cell accumulations (T cell nests) was developed using CD8, PD-1, CD112R, and Ki67 multiplex fluorescence immunohistochemistry. To evaluate the clinical significance of these parameters, a cohort of 523 colorectal cancers with clinical follow-up data was analyzed. Spatial analysis of locally enriched CD8+ T cell density and cell-to-cell contacts identified T cell nests in the tumor microenvironment of colorectal cancer. CD112R and PD-1 expressions on CD8+ T cells located in T cell nests were found to be elevated compared with those on CD8+ T cells in all other tumor compartments (P < .001 each). Although the highest mean CD112R expression on CD8+ T cells was observed at the invasive margin, the PD-1 expression on CD8+ T cells was elevated in the center of the tumor (P < .001 each). Across all tissue compartments, proliferating CD8+ T cells showed higher relative CD112R and PD-1 expressions than those shown by non-proliferating CD8+ T cells (P < .001 each). Integration of all available spatial and immune checkpoint expression parameters revealed a superior predictive performance for overall survival (area under the curve, 0.65; 95% CI, 0.60-0.70) compared with the commonly used CD8+ tumor-infiltrating lymphocyte density (area under the curve, 0.57; 95% CI, 0.53-0.61; P < .001). Cytotoxic T cells with elevated CD112R and PD-1 expression levels are orchestrated in T cell nests of colorectal cancer and predict favorable patient outcomes, and the spatial nonredundancy underlies fundamental differences between both inhibitory immune checkpoints that provide a rationale for dual anti-CD112R/PD-1 immune checkpoint therapy.
Yang Cheng, Mandelkow Tim, Bady Elena, Raedler Jonas B, Simon Ronald, Sauter Guido, Lennartz Maximilian, Büscheck Franziska, Luebke Andreas M, Dum David, Menz Anne, Höflmayer Doris, Weidemann Sören, Fraune Christoph, Lebok Patrick, Uhlig Ria, Bernreuther Christian, Jacobsen Frank, Clauditz Till S, Wilczak Waldemar, Minner Sarah, Burandt Eike, Steurer Stefan, Blessin Niclas C
2023-Jan-10
CD112R, T cell nests, colorectal cancer, multiplex fluorescence IHC, spatial analysis
