This observation led to the hypothesis that senescent tumor cells play a role in inhibiting intratumoral immune cell infiltration.Īdvanced CRC remains incurable despite therapeutic improvements like the incorporation of targeted therapy into chemotherapy. In subsequent studies, we found that immune cells could not infiltrate tumor tissues and were located around senescent tumor cells in colorectal cancer (CRC). In our previous study, senescent tumor cells were shown to play an important role in cancer progression: senescent tumor cells are actively involved in the collective invasion and metastasis via CXCL12/CXCR4 signaling. Although several studies have suggested that senescent stromal fibroblasts could promote the proliferative and metastatic properties of adjacent tumor cells through the senescence-associated secretory phenotype (SASP), whether naturally occurring senescent tumor cells in malignant tumors could mediate similar protumorigenic effects has not yet been fully elucidated. Nonetheless, senescent tumor cells have been found not only in premalignant tumors but also in developed malignant tumors. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.Ĭellular senescence, a state of irreversible cell cycle arrest in response to diverse stimuli, including telomere attrition, genotoxic damage, and oncogene activation, is historically considered to be an essential anticarcinogenic barrier in normal cells. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8 + T cell activation. Senescent tumor cells inhibit CD8 + T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Here, it is shown that intratumoral infiltration of CD8 + T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Cellular senescence can either support or inhibit cancer progression.
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