Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS

Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS

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Introduction: Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed.We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option.In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients.

Methods: Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured oljelampe mesothelioma cell lines.We used immune profiling by multiplex flow cytometry to characterize different populations of immune cells.In particular, we determined frequencies of T cell subsets that showed single and combinatorial expression of multiple markers that signify T cell activation, maturation and inhibition.

Therapy-induced T cell reactivity was assessed in peptide/MHC multimer stainings using mesothelin as a prototypic target antigen with confirmed expression in the clinical tumor lysate preparation.T cell receptor (TCR) diversity was evaluated by TCRB gene PCR assays.Results: We observed an increase in the numbers of B cells, CD4 and CD8 T cells, but not NK cells at 6 weeks post-treatment.

The increases in B and T lymphocytes were not accompanied by major changes in T cell reactivity toward mesothelin nor in TCRB diversity.Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks).Discussion: DC immunotherapy using allogeneic tumor lysate resulted in enhanced frequencies of B cells and T cells in blood.

We did not detect a skewed antigen-reactivity of peripheral CD8 T cells.Interestingly, frequencies of CD4 T cells expressing activation markers and PD-1 were increased.These findings indicate a systemic activation of the adaptive immune response and may guide future immune monitoring kt196 torque converter studies of DC therapies.