PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

Abstract

Programmed cell death 1 (PD-1) is an immuno-checkpoint receptor which is primarily expressed on T cells, monocytes, natural killer cells and macrophages. Programmed death-ligand 1 (PD-L1) is the primary ligand of PD-1 and is constitutively expressed on antigen presenting cells, mesenchymal stem cells and bone marrow-derived mast cells. In addition, PD-L1 is also expressed on a wide range of tumor cells, including lung cancer, breast cancer and melanoma. PD-1 and PD-L1 are important members of the immunoglobulin super-family and participate in immune regulation. In the present study, the immune-suppressive effects of a number of tumor cell lines were determined. The breast tumor cell lines MCF-7 and MDA-MB-231 displayed the largest inhibitory effects on T-cell activation and cytokine secretion in a co-culture system. The HepG2, A549 and A375 cells displayed limited inhibitory effects. MCF-7 and MDA-MB-231 cells expressed the highest level of PD-L1 among the cells used, which may explain their higher immuno-suppressive effects. Compound A0-L, a small molecule inhibitor of the PD-1/PD-L1 interaction, restored T cell functions. Additionally, it was demonstrated that the tumor cells with higher levels of PD-L1 expression suppressed signaling pathways involved in T-cell activation, such as the T-cell receptor- zeta chain of T cell receptor associated protein kinase ZAP70-RAS-GTPase-extracellular-signal-regulated kinases and CD28-PI3K-Akt serine/threonine kinases pathways. These findings suggest that tumor cells with higher expression levels of PD-L1 may exhibit higher immuno-suppressive activity, and that drugs targeting the PD-1/PD-L1 interaction may have improved therapeutic effects on tumors expressing higher levels of PD-L1.

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

“…Although many immortalized cell lines may have a reduced HLA expression [ 65 , 66 , 67 ], it is conceivable that some cancer cells induce an HLA mismatch when co-incubated with hPBMCs, being from different donors. However, in line with other similar papers published in the literature [ 61 , 62 , 63 , 64 ], for all tested combinations (in our case controls and treatments with ipilimumab under high glucose and low glucose) the differences between groups are still due to the treatment conditions. Moreover, different open discussion papers are available about the role, for example, of HLA-E in co-cultures of cancer cells and PBMCs [ 68 ].…”

“…There are some limitations of this study: firstly, human leukocyte antigen (HLA)-class I molecules on tumor cells have been regarded as crucial sites where cytotoxic T lymphocytes can recognize tumor-specific antigens. HLA mismatch could be a possible limitation of co-cultures of tumor cells with hPMBCs, despite co-culture models often being used and recommended in preliminary cell-lymphocytes interaction studies, as reported in the literature [ 61 , 62 , 63 , 64 ]. Although many immortalized cell lines may have a reduced HLA expression [ 65 , 66 , 67 ], it is conceivable that some cancer cells induce an HLA mismatch when co-incubated with hPBMCs, being from different donors.…”

Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

“…PD-L1, the primary ligand of PD-1, is expressed in several cancer cells, including those of the breast [40,41]. Thus, we investigated whether the ablation of ObR may also modulate PD-L1 expression in all employed experimental models.…”

Cardiotoxicity danger in immunotherapy

“…One of the defense mechanisms used by cancer cells is activation of PD‐L1 receptor in the tumor environment, which causes suppression of immune cells. PD‐L1 or PD‐L2 may be present on cancer cells, mesenchymal stromal cells, and antigen presenting cells (APCs) 6 . Tumor infiltrated T cells (TILs) may undergo elimination via apoptosis or remain in anergy leading to exhaustion due to the interaction of the PD‐1 molecule present on their surface with PD‐L1 or PD‐L2 ligands found on cancer cells and APCs (Figure 3a).…”