Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS
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 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 studies of DC therapies.
CITE THIS COLLECTION
REFERENCES
- https://doi.org//10.1038/nrc.2017.42
- https://doi.org//10.1016/j.lungcan.2015.05.014
- https://doi.org//10.1164/rccm.201608-1755CI
- https://doi.org//10.1126/science.1232227
- https://doi.org//10.1080/2162402X.2015.1009285
- https://doi.org//10.1080/2162402X.2015.1082028
- https://doi.org//10.1164/rccm.200909-1465OC
- https://doi.org//10.1164/rccm.201508-1573OC
- https://doi.org//10.1158/1078-0432.CCR-17-2522
- https://doi.org//10.1016/0022-1759(84)90340-5
- https://doi.org//10.1093/intimm/dxq440
- https://doi.org//10.1182/blood-2016-06-718619
- https://doi.org//10.1038/sj.leu.2403202
- https://doi.org//10.1038/leu.2012.246
SHARE
Usage metrics
![Frontiers in Immunology](https://s3-eu-west-1.amazonaws.com/876az-branding-figshare/frontiers/logo.png)
AUTHORS (10)
CATEGORIES
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity