Circulating CD137(+) T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

PURPOSE: CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137(+) T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137(+) T cells in the improvement of patients' selection for immunotherapy treatment. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137(+) T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137(+) T cells was also examined in different tumor settings. RESULTS: The percentage of CD137(+) T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8(+)CD137(+) T cell population. The high frequency of CD137(+) and CD8(+)CD137(+) T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3(+)CD137(+)PD1(+) lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137(+) and CD8(+) T cells. CONCLUSIONS: We propose the CD137(+) T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.