Background

Immunotherapy is changing the landscape of cancer treatment. To improve patient outcomes through precision medicine, therapy decisions need to be made based on patient-specific immunological signatures, but clinically validated biomarkers for this purpose are currently lacking.  We have recently shown that in melanoma patients who respond to immunotherapy, one cycle of checkpoint inhibitor treatment is associated with a bifurcated outcome in the T cell receptor (TCR) repertoire of circulating T cells, specifically with an increase either in clonality or in diversity.  We have also identified a subset of CD8⁺ effector memory T cells (T_IE) in peripheral blood that are associated with an increase in overall survival.  To understand better the biology underpinning our observations, we investigated the clinical correlates associated with this immune signature.  The aim of this study is to ascertain the impact of patient age on T_IE cell evolution and TCR repertoire evolution under the selective pressure of immunotherapy.

Method

Fifty metastatic melanoma patients treated with first-line anti-PD1 based immunotherapy were included.  We used flow cytometry and TCR sequencing respectively to correlate changes in peripheral T cell subset dynamics and the T cell receptor repertoire to age in pre-treatment (T0) samples, and after one cycle (W3) of therapy.

Results

In the T0 samples, we found a significant correlation (p=0.005, R²=0.15) between T_IE cell abundance and age, but this relationship was not maintained at W3 (p=0.09, R²=0.05) when T_IE expansion was proportional to tumour burden response. After the first cycle of immunotherapy, two opposing patterns of TCR repertoire rearrangement correlated with age. In older patients (≥ 70 years) peripheral T cell evolved to increased repertoire clonality, whereas in younger patients (< 70 years) the repertoire evolved to increase diversity (p=0.03).

Conclusion

We demonstrate age-specific differential immune-awakening patterns induced by immunotherapy in cancer patients. These findings will have important ramifications for both biomarker development and planning future personalised therapeutic strategies.

Impact statement

T_IE cells could be used as early prognostic biomarkers for young and elderly patients, however TCR repertoire analysis must be contextualised to patients’ age. Therapeutic strategies aiming to boost peripheral TCR repertoire diversification to recognise tumour neoantigens might be ineffective in elderly patients.