Decreased levels of circulating cytokines VEGF, TNF-β and IL-15 indicate PD-L1 overexpression in tumours of primary breast cancer patients

Abstract

Programmed death ligand 1 (PD-L1) overexpression has been associated with poor clinical outcomes in several human cancers whose increased malignant behaviour might be related to PD-L1 mediated systemic immunological tolerance. This study aims to verify if circulating cytokines may serve as a proxy for non-invasive identification of sensitive prognostic biomarkers reflecting tumour and its microenvironment. Immunohistochemistry was used to measure PD-L1 expression in tumour tissue sections of 148 chemonaïve breast cancer (BC) patients. The panel of 51 cytokines was analysed using multiplex bead arrays. High PD-L1 expression in tumours was associated with shorter progression-free survival (HR 3.25; 95% CI 1.39–7.61; P = 0.006) and low circulating levels of three multifunctional molecules; VEGF, TNF-β and IL-15 (P = 0.001). In multivariate analysis, patients with low VEGF had 4.6-fold increased risk of PD-L1 overexpression (P = 0.008), present in 76.5% of patients with all these three cytokines below the median (vs. 35.6% among the others; P = 0.002). The area under the curve value of 0.722 (95% CI 0.59–0.85; P = 0.004) shows that this combination of cytokines has a moderate ability to discriminate between PD-L1 high vs. PD-L1 low patients. Plasma cytokines, therefore, could serve as potential non-invasive biomarkers for the identification of high-risk BC cases.

Exercise-induced IL-15 acted as a positive prognostic implication and tumor-suppressed role in pan-cancer

“…Currently, rare studies have checked the IL-15 expression in pan-cancer using tissue microassays except in those databases. Cierna et al (2021) found that decreased levels of circulating IL-15 suggested PD-L1 overexpression in tumors of primary breast cancer patients and poor prognosis. Krizia et al ( Cierna et al, 2021 ) reported that higher IL-15 levels would lead to better outcomes in prostate cancer, which is consistent with our findings.…”

“… Cierna et al (2021) found that decreased levels of circulating IL-15 suggested PD-L1 overexpression in tumors of primary breast cancer patients and poor prognosis. Krizia et al ( Cierna et al, 2021 ) reported that higher IL-15 levels would lead to better outcomes in prostate cancer, which is consistent with our findings. Margolin et al (2018) recently found that the injection of IL-15N72D: IL-15RαSu/IgG1 Fc complex could reduce cancer growth, induce NK cell expansion and improve survival in patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer.…”

“…However, we also found that mRNA expression levels of IL-15 played a cancer-promoting role in GBM, OSCC, LGG, THYM, LIHC, LAML, PAAD, and GBMLGG. These suggest that the mechanism of IL-15 in cancers are complex and IL-15 may play a negative role in certain cancer types in a specific condition, which will need to be further tested in the future ( Waldmann, 2014 ; Fiore et al, 2020 ; Cierna et al, 2021 ). For example, overexpression of IL-15 mRNA is associated with clinical staging and metastasis in cutaneous T-cell lymphoma ( Döbbeling et al, 1998 ), but we found from the Kaplan-Meier database that IL-15 is more likely to be a protective factor for patients with SKCM.…”

Circular RNA‐associated ceRNA network involved in HIF‐1 signalling in triple‐negative breast cancer: circ_0047303 as a potential key regulator

“… 36 It has been recently shown that VEGF signalling exerts immune suppressive effects in BC tumours. 37 In hypoxia, the eukaryotic initiation factor 4E type 2 (EIF4E2 ) embarks on the translation of HIF‐2α‐bound mRNAs that contain hypoxia response elements. 38 Silencing of EIF4E2 in MDA‐MB‐231 triple‐negative cell line indicated a remarkable decrease in tumour cell migration and invasion during hypoxia.…”

Epstein‑Barr virus as a promoter of tumorigenesis in the tumor microenvironment of breast cancer (Review)

“…The expression by cancer cells of programmed death ligand 1 (PD-L1), also known as CD274, plays a crucial role in the suppression of the immune system response; thus, it has been considered a therapeutic target in BC when overexpression is identified. However, PD-L1 is still under investigation due to the variability in expression and results as shown in different studies ( 98 ).…”