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 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. (c) 2021 The Authors. Published by Elsevier Ltd.

Automated summary

This study found that immunotherapy can induce changes in the clonality and diversity of the peripheral T cell receptor repertoire in patients with melanoma. Age has an impact on treatment response, with different age groups showing different response patterns.