T cell receptor next-generation sequencing reveals cancer-associated repertoire metrics and reconstitution after chemotherapy in patients with hematological and solid tumors

Abstract

The dynamics of immunoaging and the onset of immunoparesis in healthy individuals and cancer patients has been controversially discussed. Moreover, the role of chemotherapy on T cell regeneration needs further elucidation in light of novel immunotherapies that have become standard of care for many elderly cancer patients. We used next-generation immunosequencing to study T cell receptor (TCR) repertoire metrics on 346 blood samples from healthy individuals and cancer patients producing a dataset with around 8.8 million TCR reads. This analysis showed that decline of T cell diversity and increase in T cell clonality is a continuous process beginning in healthy individuals over 40 years of age. Untreated patients with both hematological and solid tumors showed blood TCR repertoires with significantly lower diversity and higher clonality as compared to healthy individuals across all decades. Loss in T cell diversity was essentially driven by a loss in richness in aging healthy individuals, while in cancer patients a loss in repertoire evenness was an additional contributing factor. Interestingly, chemotherapy did not impair the regeneration of blood TCR repertoire diversity to pre-treatment age-specific levels. Surprisingly, even patients over the age of 70 years receiving highly T cell toxic therapies reestablished their pre-treatment T cell diversity suggesting rebound thymic activity rather than recovery of T cell counts by peripheral expansion only. Taken together, these data suggest that human TCR repertoire metrics gradually deteriorate in the aging individual, but age-specific TCR metrics are restored after T cell depleting therapy even in elderly cancer patients.