Telomeres and Cellular Senescence in Cancer Development

Many benign human neoplasms and cancer precursor lesions cease growth because cells within these lesions have undergone a proliferative arrest called oncogene-induced senescence (OIS) . Our studies revealed that OIS is activated by a DNA damage response and stabilized due to the formation of dysfunctional telomeres. We therefore called this response, or any response that is activated or stabilized by dysfunctional telomeres, telomere dysfunction-induced senescence (TDIS; Suram et al., 2012, EMBO J). We discovered that the great majority of cells in several benign human tumors and inactive cancer precursor lesions, including melanocytic nevi, ductal hyperplasia of the breast, and colonic adenomas, display hallmarks of TDIS, supporting the model that OIS, stabilized by telomere dysfunction, suppresses malignant cancer progression in humans. However, the fact that a subset of these lesions can progress to invasive cancers also raises the possibility that senescence is an unstable cell state and that cells can escape from senescence after a period of inactivity. Indeed, we subsequently discovered that cells escape from cellular senescence after a prolonged period of inactivity by at least two distinct cell-autonomous mechanisms: 1) by derepression of hTERT expression (Patel, et al., 2016, PNAS) and 2) by upregulation of the transcription factor PUO2F2/OCT2 (Martinez-Zamudio et al., 2023, Cell Genomics, Figure 4). Another primary factor that increases the risk for OIS escape is the prolonged presence of SCs within cancer precursor lesions. Since SCs are usually eliminated by immune cells, such as CD8 T cells, shortly after they are generated, we are now testing the hypothesis that tumor-infiltrating CD8 T cells also undergo senescence within human cancer precursor lesions, which causes them to lose function and fail to eliminate SCs within early neoplastic lesions. Our study will provide novel and critical insights into the contributions of CD8 T cell senescence to malignant cancer progression and reveal new strategies to improve CD8 T cell function for cancer therapy.