gms | German Medical Science

Objective: Immunosuppressive lymphocyte populations are a key factor in tumor immune escape resulting in increased tumor progression and recurrent disease. Recently, both B and T cell subsets were shown to produce immunosuppressive, extracellular adenosine (ADO) by the ectonucleotidases CD39 and CD73. Moreover, inhibition of the checkpoint molecule Programmed-cell-death-protein 1 (PD-1) showed promising results in different cancers. Chemoradiotherapy (CRT) is part of multimodal treatment but may promote immunosuppression in head and neck squamous cell carcinoma (HNSCC) and glioblastoma patients. In a recent study we tested the influence of CRT on lymphocyte functions in HNSCC patients.

Methods: Mononuclear cells were collected prospectively from HNSCC patients before and after CRT (n=18), a second cohort sampled several months after CRT (n=14) and from healthy donors. The phenotype of lymphocytes was analyzed by multicolor flow cytometry. Further, function of B cells was determined by ATP luminescence assay and mass spectrometry. We hypothesize that our findings can be reproduced in glioma patients and are therefore currently collecting samples.

Results: B cells were diminished in absolute number and frequency in HNSCC patients after CRT. While platinum-based chemotherapy decreased the expression of CD39, methotrexate led to a functional increase in CD39 expression and production of immunosuppressive ADO. The production of ADO correlated strongly with the surface expression of CD39. T-helper cells expressing CD39 were elevated after CRT from 12,6 ± 5,1% to 23 ± 11,6%. Moreover, the frequency of CD4+PD-1+ T cells was significantly higher after CRT (p=0.0004).

Conclusion: CRT reduces adenosine-producing B cells number and, consequently, potential immunosuppression within the tumor environment, while there is a contrary effect regarding CD39 and PD-1 expression in CD4+ T cells. The capacity to suppress CD4+ T cells is promoted by methotrexate treatment amplifying anti-inflammatory effects. Our results might help to understand how CRT can influence the immune system and may therefore help to orchestrate standard oncologic therapy with new immune modulating approaches. Effects of radiation and temozolomide in glioblastoma patients, where similar immune escape mechanisms are known to occur, are not yet fully understood. Analysis of lymphocytes in glioma patients will be performed, to evaluate effectiveness of ADO pathway modulation and PD-1 inhibition.