Dynamic changes in peripheral T cell populations predict response to PD-1 immunotherapy

Immunotherapy has revolutionised melanoma treatment, but most patients still die of disease. Blood-based biomarkers to identify check-point inhibitors (CPI) response early during treatment will provide useful and easily accessible guidance for clinical decisions. We analysed peripheral blood mononuclear cells (PBMCs) and plasma cell-free DNA (cfDNA) of 26 stage IV melanoma patients before (before the 1stdose, T0) and during (at week 3, W3) therapy with 1stline CPI (anti-PD1 or anti-PD1 plus anti-CTLA-4 drugs) to study circulating T lymphocyte subsets and T cell receptor beta (TCRβ) repertoire. Responses were determined at 12 weeks (W12) as per standard practice. In PBMCs, we used high dimensional flow cytometry to quantify 20 T cell subpopulations and analysed if their changes over time were prognostic. We found that a CD8+ T cell subpopulation (Teff) expanded at W3 in patients who then responded to therapy (N=13), but not in patients who progressed (N=13) (P<0.001). In a subgroup of patients we analysed the pattern of T cell turnover, which is also indicative of T cell clearance. Assessed indirectly by means of cfDNA TCRβ sequences, we found that T cell turnover correlated with Teff expansion (P=0.013).