Significance: A decline in the diversity of the T-cell receptor repertoire owing to thymic involution has been implicated as causing defective immune responses in the elderly. By applying next-generation sequencing of replicate TCRB libraries from highly purified T-cell subsets, and using nonparametric statistical analysis, we obtain estimates of repertoire richness in the young adult that are higher than previously reported. Although contracting with age, the repertoire remains highly diverse. These data challenge the paradigm that thymic rejuvenation is needed to maintain diversity and prevent immune incompetence in the elderly. However, we observe an increasing inequality of clonal sizes with age even among naïve T cells. This clonal selection could result in biased and possibly autoreactive immune responses.

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.