T cell immune awakening in response to immunotherapy is age-dependent

Abstract

Background: Precision immuno-oncology approaches are needed to improve cancer care. We recently demonstrated that in patients with metastatic melanoma, 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 (T_IE 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 patients with metastatic melanoma treated with first-line anti-PD-1 ICB were included. We analysed TCR repertoire and peripheral T_IE cell dynamics by age before treatment (T0) and after the first cycle of treatment at week 3 (W3).

Results: We observed a correlation between T_IE 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 patients with melanoma are age-related and may impact patient response to ICB, and thus have implications for biomarker development and planning of personalised therapeutic strategies.

Keywords: Age; Immune-checkpoint blockade; Immunotherapy; Melanoma; T cell; T cell receptor.