High PD-L1/CD274 Expression of Monocytes and Blood Dendritic Cells Is a Risk Factor in Lung Cancer Patients Undergoing Treatment with PD1 Inhibitor Therapy.

Dagmar Riemann,Barbara Seliger,Wolfgang Schütte,Miriam Möller,Steffi Turzer

doi:10.3390/cancers12102966

Dagmar Riemann, Barbara Seliger + Show 3 more

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https://doi.org/10.3390/cancers12102966

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Abstract

Simple SummaryTumor cells can evade destruction via immune cells by expressing coinhibitory membrane molecules, which suppress antitumoral immune responses. Immune checkpoint inhibitor therapy acts by blocking these inhibitory pathways. Although this type of immunotherapy has shown promising results for selected cancer patients during recent years, an important challenge remains to identify baseline characteristics of patients who will mostly benefit from such therapy. The aim of our study was to assess the expression of the coinhibitory molecule PD-L1/CD274 on different antigen-presenting cells (monocytes and dendritic cell subsets) in the peripheral blood of 35 patients with nonsmall cell lung cancer undergoing checkpoint inhibitor therapy. CD274 expression correlated with therapy response and the survival of patients. Tumor patients with high CD274 expression levels of antigen-presenting cells in blood rarely responded to checkpoint inhibitor therapy. Our results implicate that a high CD274 expression in monocytes and dendritic cell subsets is a risk factor for therapy response.The aim of this study was to investigate the expression of the coinhibitory molecule PD-L1/CD274 in monocytes and dendritic cells (DC) in the blood of lung cancer patients undergoing PD1 inhibitor therapy and to correlate data with patient’s outcome. PD-L1/CD274 expression of monocytes, CD1c+ myeloid DC (mDC) and CD303+ plasmacytoid DC (pDC) was determined by flow cytometry in peripheral blood at immunotherapy onset. The predictive value of the PD-L1/CD274-expression data was determined by patients’ survival analysis. Patients with a high PD-L1/CD274 expression of monocytes and blood DC subpopulations rarely responded to PD1 inhibitor therapy. Low PD-L1/CD274 expression of monocytes and DC correlated with prolonged progression-free survival (PFS) as well as overall survival (OS). The highest PD-L1/CD274 expression was found in CD14+HLA-DR++CD16+ intermediate monocytes. Whereas the PD-L1/CD274 expression of monocytes and DC showed a strong positive correlation, only the PD-L1/CD274 expression of DC inversely correlated with DC amounts and lymphocyte counts in peripheral blood. Our results implicate that a high PD-L1/CD274 expression of blood monocytes and DC subtypes is a risk factor for therapy response and for the survival of lung cancer patients undergoing PD1 inhibitor therapy.

Highlights

Promising benefits of immunotherapy, in particular those targeting the immune checkpoint proteinsPD1 and Programmed cell death 1 ligand 1 (PD-L1), have been shown in lung cancer patients in recent studies
Our results show that PD-L1/CD274 expression of monocytes and dendritic cells (DC) was positively correlated suggesting common ways of regulation in the different cell types
Our results show that CD14+ CD16+ intermediate monocytes with a high HLA-DR intensity expressed the highest PD-L1/CD274 levels

Summary

Introduction

PD1 and PD-L1, have been shown in lung cancer patients in recent studies. Immune checkpoints are proteins that restrict physiologic immune cell responses in order to maintain immune homeostasis and protect host tissues from unnecessary damage due to excessive inflammation. Since many tumors can express PD-L1/CD274, the rationale of the PD-L1 pathway blockade is to inhibit the immunosuppressive PD-L1/PD1 interaction between tumor cells and T cells that hampers the activity of CD4+ and CD8+ T cells thereby enhancing T cell-mediated antitumor activities [2,3]. Selected patients with advanced non-small cell lung cancer (NSCLC) profit from the treatment with the PD1 inhibitors pembrolizumab or nivolumab in first-or second-line settings. Treatment with immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse effects [4]. Durable responses are only observed in a minority of patients and primary, adaptive and acquired therapy resistances are common [4,5,6]

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