Telomere Shortening Induces T-cell Dysfunction and Squamous Cell Cancers

Short telomere syndromes (STS) are diseases of premature aging that are associated with an increased risk of developing cancer and are hypothesized to arise due to chromosome instability. To test this hypothesis, Schratz and colleagues examined the malignancies that arose in a large cohort of patients with STS over a 20-year period and showed that cancers commonly associated with aging were rarely diagnosed in this patient population. Instead, the majority of cancers diagnosed were squamous cell carcinomas (SCC), and genome sequencing revealed that these tumors had inactivated p53 and acquired telomere maintenance mechanisms to avoid telomere crisis and apoptosis. Moreover, the extent of tumor mutation burden and structural variant burden was similar to or lower than that found in sporadic head and neck SCC, indicating that genomic instability likely does not contribute to the development of SCC in patients with STS. Nearly all patients with STS had shorter telomeres in SCC tumors than adjacent normal tissue and notably harbored a T-cell immunodeficiency when diagnosed with cancer, suggesting that shortened telomeres may inhibit T-cell antitumor function. Further evaluation of short telomere length on T cell–dependent cancer immunity using a mouse model lacking telomerase RNA (TR^–∕–), which has shortened telomeres after successive breeding, demonstrated T-cell dysfunction similar to that seen in patients with STS. Immunogenic tumor cells implanted in these mice were suppressed followed by relapse, while tumor growth remained suppressed in control mice. Mechanistically, analysis of tumor-infiltrating lymphocytes demonstrated similar levels of CD4⁺ and CD8⁺ T-cell infiltration in control and TR^–∕– mice 7 days after implantation, but at 30 days after implantation, the populations of intratumoral CD4⁺ and CD8⁺ T cells were markedly diminished in the TR^–∕– mice, likely leading to this observed tumor relapse. In summary, this study describes a novel mechanism by which telomere shortening promotes the development of cancer via T-cell immunodeficiency.

Schratz KE, Flasch DA, Atik CC, Cosner ZL, Blackford AL, Yang W, et al. T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers. Cancer Cell 2023;41:807–17.

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