Immune checkpoints in aggressive breast cancer subtypes

Abstract

Immune checkpoints are molecules referred to inhibitory pathways in the immune system that play a pivotal role in prevention of autoimmunity and oncogenesis. The aim of the study was to evaluate expression levels of selected immune checkpoints- PD-1 (programmed cell death protein 1), and PD-L1 (programmed cell death 1 ligand 1) in breast cancer patients, suitable for breast conservation and sentinel node biopsy and determine their associations with clinicopathological factors.Expression of the genes coding for PD-1 and PD-L1 was analyzed in formalin-fixed paraffin-embedded specimens using real-time PCR. mRNA expression levels were determined using beta actin (ACTB) as an endogenous control. There was a trend towards significance between higher PD-1 and PD-L1 levels in triple negative breast cancers (p=0.1). Higher PD-L1 expression was also found in aggressive breast cancer subtypes e.g. triple negative and HER2 (human epidermal growth factor receptor 2) -positive as compared with subtypes with better prognosis such as luminal A and luminal BHER2-negative (p=0.05). There was a trend towards significance in higher PD-1 levels in triple negative and HER-2 positive breast cancers (p=0.1). A statistically significant difference was found between PD-L1 expression and tumor grade (p=0.01). Elevated PD-L1 levels were noted in G3 tumors. Immunogenicity appears to be gaining importance in triple negative and HER2-positive molecular subtypes of breast cancer, and the results in this study provide a basis for further investigation into the role of immune checkpoints in breast cancer.

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…In addition, it has been reported that PD‐L1 is differentially expressed across different BC subtypes. In particular, available evidence consistently reports greater expression of PD‐L1 in the TN subtype (up to 60% of PD‐L1 expression) compared with non‐TNBC . These data appear to be coherent with the observation that PD‐L1 tumor expression is positively associated with stromal tumor‐infiltrating lymphocytes (TILs) in this BC subtype , which is known to be more frequently infiltrated by stromal TILs than non‐TNBC , as summarized in Table , thus possibly suggesting that these two immune biomarkers tend to run parallel.…”

“…Data on PD‐L1 expression in HER2‐positive BC are more controversial. In fact, whereas in some studies HER2 positivity has been correlated with higher expression of PD‐L1 (up to 50%) compared with HER2‐negative BC , others failed to report any difference .…”

“…Several studies evaluated PD‐L1 expression according to baseline clinicopathological features of patients with BC, consistently reporting a correlation between higher PD‐L1 expression and unfavorable classic prognostic factors, particularly poorer histological grade , higher proliferative index , more advanced N stage , larger tumor size , and younger age at BC diagnosis .…”

Type Iγ phosphatidylinositol phosphate kinase regulates PD-L1 expression by activating NF-κB

“…Our current results further showed that loss of PIPKIγ suppressed the expression of PD-L1, which likely also contributes to the inhibition of cancer progression caused by PIPKIγ depletion, because loss of PD-L1 expression makes tumor cells much less defensive to anti-tumor immunity. Additionally, recent studies suggested a correlation between PD-L1 and the epithelial-to-mesenchymal transition (EMT) in solid tumors to regulate cancer metastasis [50, 51–54]. The pro-metastatic process EMT may induce breast cancer PD-L1 expression and immune suppression in a PI3K/AKT and/or MEK/ERK dependent manner.…”

A review of the importance of immune responses in luminal B breast cancer

“…51 Higher PD-1 and PD-L1 RNA levels were seen in TNBC and HER-2 C tumors compared with luminal A and luminal B HER-2 ¡ tumors; expression levels increased with tumor grade suggesting increasing immune suppression with disease progression. 52 Studies are currently ongoing to evaluate anti-PD-1 and anti-PD-L1 antibodies in metastatic BC.…”