CD155 expression in human breast cancer: Clinical significance and relevance to natural killer cell infiltration
Introduction
CD155, originally recognized as the poliovirus receptor, is a transmembrane glycoprotein receptor which belongs to the Nectin family of the immunoglobulin super-family. These proteins function as adhesion molecules and they are involved in cell-cell contact [1]. Under normal physiological conditions, CD155 is located on the cell surface. It is highly expressed on dendritic cells, fibroblasts and endothelial cells. Other cells can also express CD155 in pathophysiological situations like tumor cells including ovarian carcinoma, lung adenocarcinoma, glioblastoma, and colorectal carcinoma [[2], [3], [4], [5], [6]]. Indeed, CD155 interacts with regulatory receptors CD226 (expressed on natural killer (NK) cells, monocytes and CD4+ T cells) and CD96. While CD155-CD226 engagement stimulates NK cell cytotoxicity and T cell response [7], CD155 binds to CD96 resulting in NK cell function inhibition. It has a high affinity for a T cell regulatory transmembrane surface protein referred to as TIGIT (T cell immunoglobulin and ITIM domains) [8]. Nevertheless, this balance is often disrupted in the tumor microenvironment (TME), inducing tumor immunosuppression [9].
As is well known, the TME is designed by a number of factors derived from the tumor cells which draw and regulate a variety of cells, including immune cells and stromal cells [10,11]. The immune cells are the main cell types of the TME, indeed, tumor-infiltrating lymphocytes (TILs) belong to a largely studied population and their clinical importance was established in a series of human cancers [12]. Accordingly, natural killer (NK) cells make a small portion of the TILs [13]. As innate immune effectors, NK cells display a spontaneous cell-mediated cytotoxicity in patients with cancer, underlying their distinctive function in the control of tumor cell expansion as well as cancer immune surveillance. Further, the prognostic relevance of tumor infiltrating NK cells (NK-TILs) has been reviewed and correlated with variable clinical outcome in a wide variety of cancers [14]. As CD155 is a stress-induced ligand of NK-TILs co-stimulatory receptor CD226, CD226–CD155 interaction is crucial for the NK cell-mediated lysis of cancerous cells and for metastasis suppression [15].
Breast cancer (BC) is one of the most commonly diagnosed neoplasm and cause responsible for cancer mortality among women in the world. It has long been demonstrated that BC tissue is invaded by a mixed population of immune cells, most remarkably, a substantial lymphocytic infiltration was often observed [16]. In BC, the importance of NK cells as infiltrating immune cells is increasingly being recognized, however, only a limited amount of data is available on NK-TILs in BC [17]. Further, the mechanisms of escape from NK cell mediated immunity were proven to be at play in BC patients. Notably, Mamessier and colleagues [18] reported that breast tumors were able to shape their environments to evade NK cell immune response against cancer and that breast tumors evolution require NK cell dysfunction. Accordingly, breast tumor cells alter NK cell functions through the modulation of their surface receptors, a mechanism observed in a variety of human malignancies [[19], [20], [21], [22], [23]]. These alterations are related to invasive characteristics and worse prognosis. Altogether, these data imply that BC evolution is related to anti-tumor immunity efficiency and specifically to NK cells.
CD155 is weakly expressed in several normal human tissues, but it is frequently over expressed in different human neoplasms. Moreover, the clinicopathological analysis shows that CD155 overexpression is associated with cancer evolution and unfavorable prognosis [[3], [4], [5]]. To the best of our knowledge, no previous studies have investigated the prognostic value of CD155 protein expression, nor its association with NK cell infiltration in BC.
The aim of this study is to investigate the clinical significance of CD155 expression in invasive BC tissues as a potential target stress molecule for NK cells. We tempted to clarify the prognostic value of the concomitant presence of CD155 and NK-TILs on disease outcome and survival in women patients with BC. Substantially, the assessment of tumor infiltrating NK cells is evaluated as CD56+ lymphocytes tissues count and distribution. Basically, CD56 is the most important tissues cell biomarker for distinguishing NK cells from others lymphocytes populations [24].
Section snippets
Patients and tumor samples
This is a retrospective cohort of females with invasive BC. Cancer tissues were obtained from women originating from the south area of Tunisia, diagnosed with invasive breast carcinomas who underwent surgical resection at the Department of Gynecology and Obstetrics of the Hedi Chaker University Hospital (Sfax, Tunisia). Patients who had received neoadjuvant chemotherapy or radiation prior to surgical resection were excluded from this study. The specimens n = 158 were formalin-fixed and
Clinical-pathological characteristics of patients
The clinical-pathological characteristics of 158 breast cancer patients are summarized in Table 1. The age of patients ranged from 24 to 83 years with an average of 49.9 ± 12.8 years (median = 48). Tumor size ranged from 0.8 cm to 12 cm with a mean size of 3.8 cm ± 2 (median = 3), with 12.1% patients affected with inflammatory BC. Informative BC cases about Lymph Node involvement showed 63.5% positive cases. Lymphovascular invasion is present in 43.3% of patients. Only 14.5% were grade I BC
Discussion
The present study aimed to decipher the clinical significance of CD155 expression in breast cancer using IHC. This work is also the first study, which analyzed the prognostic relevance of CD155 together with NK cells infiltration as immune cells targeting this stress marker in this malignancy. To date, the immunoregulatory function and clinical impact of CD155 is complex and not well understood in the TME. The TME has progressively been proven to dictate aberrant tissue function, it is the main
Conclusion
In conclusion, our findings may offer early insights and contribute to the actual understanding on the impact of NK cell-activating ligands in breast cancer patients revealing that CD155 could be a promising biomarker for breast tumors progression and prognosis. However, the way CD155 localization and density are involved in the progression of this malignancy and in patients' outcome remain to elucidate. Thus, further assessment is required since CD155 localization and density are two
Grant support
This work was funded by ISESCO (Islamic Educational, Scientific and Cultural Organization) Research grant (Ref No. 2148).
Statement of human rights
We have conducted a retrospective study, for this type of study formal consent is not required.
Declaration of Competing Interest
All authors have reviewed the final version of the manuscript and approve it for publication. The authors have no conflicts of interest to declare.
Acknowledgements
The authors would like to thank all participants for their contribution and cooperation. This work was partially supported by ISESCO (Islamic Educational, Scientific and Cultural Organization) Research grant (Ref No. 2148).
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