Potential clinical implications of CD4+CD26high T cells for nivolumab treated melanoma patients

Background Nivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients’ outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe of-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will beneft from anti-PD-1 treatment avoiding unwanted side efects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies. Methods The frequency distribution of peripheral blood CD26-expressing cells was investigated employing multiparametric fow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients. Results Circulating CD4+CD26high T cells were signifcantly reduced in melanoma patients compared to healthy subjects (p=0.001). In addition, a signifcant association was observed between a low baseline percentage of CD4+CD26high T cells (<7.3%) and clinical outcomes, measured as overall survival (p=0.010) and progression-free survival (p=0.014). Moreover, patients with clinical beneft from nivolumab therapy had signifcantly higher frequencies of circulating CD4+CD26high T cells than patients with non-clinical beneft (p=0.004) at 12 months. Also, a higher pre-treatment proportion of circulating CD4+CD26high T cells was correlated with Disease Control Rate (p=0.014) and best Overall Response Rate (p=0.009) at 12 months. Interestingly, after 12 weeks (W1) of nivolumab treatment, percentages of CD4+CD26high T cells were signifcantly higher in comparison with the frequencies measured at W0 (p<0.0001), aligning the cell counts with the ranges seen in the blood of healthy subjects.