Tumor-immune cell interaction and senescence-associated molecules in colorectal carcinoma

Abstract

Cellular senescence permanently arrests the cell cycle of premalignant cells following protumorigenic stimuli, counteracting tumor progression. Senescence induction leads to phenotypic and metabolic changes and alters the interaction with the cells' microenvironment. This mediates tumor immunosurveillance but bears promalignant potential and may contribute to disease progression. Our study aims to investigate the prognostic potential of senescence markers in colorectal carcinoma (CRC) and to understand the interaction of senescent tumor cells and immune cells. Immunohistochemical markers were studied on atissue microarray (TMA) containing tumor tissue of n = 598 CRC patients and were evaluated using digital image analysis. Results were correlated with disease-specific survival (DSS) and progression-free survival (PFS). Consecutive TMA sections were stained for senescence markers and immune cell markers to analyze the spatial relation of those cell populations. Senescence was induced in CRC cell lines in vitro and co-cultures with various immune cell lines were established to study the interactions. Expression of different senescent-associated markers is associated with increased or decreased DSS and PFS. Close proximity of p21+ senescent tumor cells and CD8+ immune cells correlates with increased DSS and PFS. In vitro, senescent cells were dose-dependently eliminated by immune cells, which is facilitated via direct cell-cell contact and induction of apoptosis. Depicting the initiation of this important anti-tumor mechanism, markers of cellular senescence are of significant prognostic relevance in CRC. Moreover, our results show the pleiotropic effect of senescence in vivo. Absence as well as exceeding expression of senescence markers are associated with anegative prognosis in CRC. The impact of cellular senescence depends on the tumor microenvironment and the immunosurveillance of senescent cells. Proximity analyses of senescent cells and tumor-infiltrating immune cells have significant prognostic relevance and reflect this.