Anti-PD1 therapy has proven to be effective in various cancer types, but the overall impact of the treatment on the immune system is not yet fully understood. Therefore, we aimed in this study to discover the effects of anti-PD1 therapy on the immune system, especially on NK and NKT cells, which are less studied, but known to be involved in antitumor immune events.
Peripheral blood from immuno-oncology naive metastatic melanoma patients (n = 19) were obtained before the first infusion of anti-PD1, then 1 and 3 months later. From each time-point, complete blood counts (CBC) were obtained, and comprehensive immunophenotyping of NK, NKT, and T cells was performed. Also, 92 serum cytokines were measured using the Olink inflammation panel.
Patients were categorized into two cohorts: responders (R, n = 6, PFS=17.0 months) and progressive disease (PD, n = 9, PFS=5.0 months). 4 patients were excluded due to challenging clinical evaluation of response. CBC indicated a significant decrease in the mean frequency of lymphocytes in PD but not in the R cohort. The responders had also higher frequency of lymphocytes at 1- and 3-month time points and lower frequency of neutrophils before initiation and after 1 and 3 months of treatment. The CBC absolute counts revealed that the responders had less neutrophils and monocytes after 3 months of treatment when compared to PD. Immunophenotyping revealed no changes in the frequency of T and NK cells during treatment, however the frequency of NKTbrightcells increased significantly. Moreover, R had more NKTdimcells before and after 3 months of therapy. Also, cytotoxic CD56dimNK cells expressed increased CD25 and CD45RO after 1 month of therapy. The cytokine assay indicated that anti-PD1 significantly increased the levels of CXC-family cytokines in the serum; CXCL9, CXCL11, CXCL10. Also, IL-12B and TNFRSF9 levels were increased. Further comparison of the two cohorts showed that CXCL9 was only increased in R cohort.
Anti-PD1 therapy increases the levels of NKT cells, inflammation related chemokines in blood and the expression of markers linked to enhanced cytotoxicity of NK cells. Therefore, further studies to investigate the role of NK and NKT cells in anti-PD1 induced responses are warranted.
Clinical trial identification
Legal entity responsible for the study
Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation.
M. Hernberg, S. Mäkelä, L. Kohtamäki: Trial funding: MSD, BMS, Amgen. S. Mustjoki: Honoraria, research funding: Novartis, Bristol-Myers Squibb, Ariad, Pfizer. All other authors have declared no conflicts of interest.