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

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.

T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

“…11 Multicolor flow cytometry revealed that DC vaccination induced an increase in the number of circulating CD4 + T cells, CD8 + T cells and B cells. 12 Furthermore, the frequency of HLA-DR, PD1 and inducible T-cell costimulator (ICOS)-expressing CD4 + T cells and LAG3-expressing CD8 + T cells increased after DC vaccination. Notably, the highest frequency of HLA-DR and ICOS-expressing CD4 + T cells was found in the best responding patient.…”

“…No major treatment-associated T cell receptor (TCR) repertoire shifts were detected by analysis of TCRβ-chain complementarity-determining region 3 (CDR3) length. 12 Recent TCR sequencing studies indicated that TCRβ clone frequency and diversity are affected by immunotherapies, such as checkpoint inhibitors in pancreatic ductal carcinoma, 13 lung cancer, 14 15 and melanoma. 16 17 Hereby, TCRβ repertoire changes, including expansion or contraction of T cell clones, correlated with clinical response.…”

Genome‐wide expression profiling‐based copy number variations and colorectal cancer risk in Chinese

“…Recently, DC vaccination has been considered as promising tumor treatment. A phase‐I trial observed the impressive objective response of a tumor reduction of about 70% at 6 weeks posttreatment in a patient with malignant pleural mesothelioma by providing enhanced tumor antigen presentation with DC vaccination through the mechanism of increasing the number of B, CD4 + and CD8 + T lymphocytes in peripheral blood . Besides, the combination of transgenic T‐cell receptor‐reactive adoptive cellular therapy with DC vaccination could result in transient antitumor activity in patients with advanced sarcoma or melanoma .…”

Interdependence Between the Phenotype of Dendritic Cells and Amounts of Blood Proinflammatory Monocytes in Patients With Kidney Cancer

“…В целом у больных РП количество нДК с указанным фенотипом значительно выше, чем у лиц контрольной группы. Молекула CD83 является основным маркером ДК, относится к суперсемейству Ig и представляет собой гликозилированный трансмембранный белок с молекулярной массой около 45 кДа, принимает участие в презентации антигенов и инициации адаптивного иммунного ответа [9,26]. CD80 (или B7.1) является гликозилированным одноцепочечным белком с молекулярной массой 60 кДа, который, совместно с CD86 (или В7.2), определяется как лиганд для CD28 и CD152 на поверхности Т-лимфоцитов [15,27].…”