T cell immune awakening in response to immunotherapy is age dependent

Background: Precision immuno-oncology approaches are needed to improve cancer care. We recently demonstrated that in metastatic melanoma patients an increase of clonality or diversity of the T cell receptor (TCR) repertoire of peripheral T cells following one cycle of immunotherapy is coincident with response to immune-checkpoint blockade (ICB). We also identified a subset of peripheral CD8+ immune-effector memory T cells (TIE cells) whose expansion was associated with response to ICB and increased overall survival. To improve our understanding of peripheral T cell dynamics we examined the clinical correlates associated with these immune signatures.
Methods: Fifty metastatic melanoma patients treated with first-line anti-PD-1 ICB were included. We analysed TCR repertoire and peripheral TIE cell dynamics by age before treatment (T0) and after the first cycle of treatment at week 3 (W3).
Results: We observed a correlation between TIE abundance and age at T0 (r=0.40), which reduced following treatment at W3 (r=0.07). However, at W3 we observed two significantly opposing patterns (p=0.03) of TCR repertoire rearrangement in patients who responded to treatment, with patients ≥70 years of age showing an increase in TCR clonality and patients <70 years of age showing an increase in TCR diversity.
Conclusions: We demonstrate that immunotherapy-induced immune-awakening patterns in melanoma patients are age-related and may impact patient response to ICB, and thus have implications for biomarker development and planning of personalised therapeutic strategies.