AUTHOR=Kellers Franziska , Fernandez Aurélie , Konukiewitz Björn , Schindeldecker Mario , Tagscherer Katrin E. , Heintz Achim , Jesinghaus Moritz , Roth Wilfried , Foersch Sebastian 

TITLE=Senescence-Associated Molecules and Tumor-Immune-Interactions as Prognostic Biomarkers in Colorectal Cancer

JOURNAL=Frontiers in Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.865230

DOI=10.3389/fmed.2022.865230

ISSN=2296-858X

ABSTRACT=background
Initiation of cellular senescence in response to protumorigenic stimuli counteracts malignant progression in (pre)malignant cells. Cells entering this terminal differentiation state adopt a characteristic senescence-associated secretory phenotype (SASP) which initiates alterations to their microenvironment and effects immunosurveillance of tumorous lesions. However, some effects mediated by senescent cells contribute to disease progression. Currently, the exploration of senescent cells´ impact on the tumor microenvironment and the evaluation of senescence as possible target in colorectal cancer (CRC) therapy demand reliable detection of cellular senescence in vivo. Therefore, specific immunohistochemical biomarkers are required. Our aim is to analyze the clinical implications of senescence detection in colorectal carcinoma and to investigate the interactions of senescent tumor cells and their immune microenvironment in vitro and in vivo.
methods
Senescence was induced in CRC cell lines by low-dose-etoposide treatment and confirmed by Senescence-associated β-galactosidase (SA-β-GAL) staining and FACS analysis. Co-cultures of senescent cells and immune cells were established. Cell viability assays, electron microscopy and live cell imaging were conducted. Various immunohistochemical (IHC) markers were studied in a cohort of CRC patients by analyzing a tissue micro array (TMA) and performing digital image analysis. Results were compared to disease-specific survival (DSS) and progression-free survival (PFS).
results
Varying expression of senescence markers was associated with in- or decreased survival of CRC patients. Proximity analysis of senescent tumor cells and cytotoxic T cells revealed a significantly better prognosis for patients in which these cell types have the possibility to directly interact. In vitro, NK-92 cells or TALL-104 cells led to dose-dependent specific cytotoxicity in >75 % of the senescent CRC cells but less than 20 % of the proliferating control CRC cells. This immune cell-mediated senolysis seems to be facilitated via direct cell-cell contact inducing apoptosis and granule exocytosis.
conclusion
Counteracting tumorigenesis, cellular senescence is of significant relevance in CRC. We show the dual role of senescence bearing both beneficial and malignancy-promoting potential in vivo. Absence as well as exceeding expression of senescence markers are associated with bad prognosis in CRC. The antitumorigenic potential of senescence induction is determined by tumor micromilieu and immune cell-mediated elimination of senescent cells.