A laminin α4-CD8(+) T cell axis shapes the prognostic impact of macrophages and regulatory T cells in early-stage colorectal cancer.

The crossing of the endothelial basement membranes (BMs) is a limiting step for leukocyte diapedesis. Heterotrimeric laminins (LMs) containing α4- and α5-chains are major BM components with opposite effects on transendothelial migration. Here, we examined whether LMα4 levels influence intratumor accumulation of specific immune cells and their impact on prognosis of early-stage colorectal cancer (CRC). Using two independent patient cohorts, we found that LMα4 expression positively correlated with intratumor infiltration of CD8(+) T cells and macrophages, but not with regulatory T (Treg) cells. Kaplan-Meier and multivariate Cox regression analyses identified CD8(+) T cell density as the strongest independent prognostic factor associated with reduced tumor relapse in both cohorts. While intratumor macrophage and Treg cell densities alone were not independently associated with prognosis, their abundance modulated outcomes specifically in tumors with high CD8(+) T cell infiltration, with macrophage-rich tumors showing improved outcomes and Treg cell-enriched tumors exhibiting worse prognosis. Analysis of The Cancer Genome Atlas (TCGA) COAD cohort confirmed the positive correlation of LMα4 expression with both CD8(+) T cell and macrophage infiltration, an association that was independent of the CRC clinical stage. Our findings suggest a subtype-specific effect for LMα4 in intratumor leukocyte infiltration, and underscore the prognostic interactions among CD8(+) T cells, Treg cells and macrophages in early-stage colorectal cancer.