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.

Fig. 1

Correlation between radiological response and peripheral biomarkers. A: Correlation (r = −0.35) between Δ_W12RECIST and Δ_W3T_IE in the melanoma patient cohort (n = 36). B: Correlation (r = −0.50) between Δ_W3RES and Δ_W12RECIST in the melanoma patient cohort (n = 22 patients with both measurements available). Data points represent individual patients. Dotted line: linear regression line.

Fig. 2

Correlation between age and peripheral T cell biomarkers. A: Correlation between age (years) and T_IE cell abundance at baseline (T0, green, r = 0.40; n = 50) and after first cycle of immunotherapy (W3, amber, r = 0.25; n = 50). B: Correlation between age (years) and TCR receptor rearrangement efficiency score (RES) at baseline (T0, red, r = −0.12; n = 28) and after the first cycle of immunotherapy (W3, black, r = −0.32; n = 28). C: Correlation between age (years) and PBMC clonality (Gini coefficient) at baseline (T0, navy, r = 0.36; n = 29), and after the first cycle of immunotherapy (W3, light blue, r = 0.39; n = 29). D: Correlation between age (years) and PBMC T cell receptor diversity (Renyi index) at baseline (T0, pink, r = −0.29; n = 29) and after first cycle of immunotherapy (W3, purple, r = −0.39; n = 29). T_IE, immune-effector T cells; PBMC, peripheral blood mononuclear cell.

Fig. 3

Relationship between age and peripheral T cell TCR repertoire re-arrangement. A: Scatter plot showing changes in peripheral TCR clonality (Gini coefficient) and diversity (Renyi index) after one cycle of anti-PD1-based treatment (W3 compared T0: Δ_W3) for patients in the age group <70 years (purple dots) and ≥70 years (green dots). The dotted line represents the linear discriminant (X0 = 0.024, slope = 0.4) for TCR re-arrangement with increased peripheral T cell clonality (hemiplot in blue) versus increased peripheral T cell diversity (hemiplot in pink). Each dot is a single patient (n = 29). B: Comparison of the number of patients with peripheral T cell re-arrangement pattern towards dominant clonality (blue) or dominant diversity in (pink) from A, according to age group (n = 29; Fisher test p = 0.03). TCR, T cell receptor.