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

Front Immunol. 2018 Sep 7;9:2034. doi: 10.3389/fimmu.2018.02034. eCollection 2018.

Abstract

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.

Keywords: T lymphocytes; dendritic cell vaccination; immune monitoring; immunotherapy of cancer; inducible T-cell co-stimulator protein; mesothelioma; programmed cell death 1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / immunology
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / immunology
  • Gene Expression
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / metabolism
  • Humans
  • Immunophenotyping
  • Immunotherapy, Adoptive*
  • Inducible T-Cell Co-Stimulator Protein / genetics*
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy*
  • Mesothelioma / etiology*
  • Mesothelioma / metabolism
  • Mesothelioma / pathology
  • Mesothelioma / therapy*
  • Mesothelioma, Malignant
  • Phenotype
  • Programmed Cell Death 1 Receptor / genetics*
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • GPI-Linked Proteins
  • HLA-DR Antigens
  • Inducible T-Cell Co-Stimulator Protein
  • Programmed Cell Death 1 Receptor
  • mesothelin