Circulating CD137 + T cells correlate with improved response to anti-PD1 immunotherapy in cancer patients

Purpose: CD137 molecule is expressed by activated lymphocytes, and in cancer patients identifies the tumor-reactive Tcells. In solid tumors, high levels of circulating CD137+Tcells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+Tcells in the improvement of patients' selection for immunotherapy treatment. Experimental design: PBMC derived from 109 metastatic cancer patients (66 patients for the identification cohort and 43 for the validation cohort) were analysed 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 analysed. The CD137+Tcell subsets and the sCD137 were correlated with the clinicopathological characteristics. The distribution of CD137+Tcells was also examined in different tumor settings. Results: The percentage of CD137+Tcells was higher in healthy donors and in those patients with a better clinical status (PS=0-1, n{degree sign}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 OS and 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 anti-cancer immunotherapy.