INTRODUCTION
Lung cancer has become a challenging health problem worldwide. More than
1.0 million people die of the disease each year [1, 2]. According to
the histopathological classification, lung cancer can be divided into
small cell lung cancer (SCLC) and NSCLC, in which NSCLC accounts for
approximately 85% and is the most common type of clinical lung cancer.
NSCLC can be subdivided into squamous cell carcinoma, adenocarcinoma and
large cell carcinoma [3-5]. In spite of the development in lung
cancer diagnosis and treatment, the overall survival of NSCLC still
remains at a low rate [6-9]. Metastasis is identified as the main
cause of lung cancer related mortalities after resection. It is
confirmed that 30-55% of NSCLC patients in early stage die from
recurrent metastatic disease after surgery with curative intent, and
only 3-10% of them can survive over 5 years with the treatment of
standard adjuvant chemotherapy [10-12]. Immune checkpoint blockade
that can promote the generation of antigen specific T cells is a newly
defined immune adjuvant therapy [13, 14]. However, most of
early-stage NSCLC tumors are removed without neoadjuvant intervention in
clinical practice [11, 15]. Current biomarkers for NSCLC such as
CYFRA21-1, CEA and CA125 are not specific and sensitive enough to
reflect the NSCLC progression. Therefore, specific biomarkers are
necessary for monitoring NSCLC development and developing targeted
treatment approaches for NSCLC.
In the progression of lung cancer, there exist multiple immune cells
infiltrating into tumor sites. Different types of these immune cells and
their products determine the fate of tumor progression. Immune cells
also play a major role in establishing metastasis of the primary tumor
to various organs [16-19]. A protective immune response against
tumor is often prevailed by the protumor response, and it eventually is
the balance or the lack of it between these two processes that determine
the fate of tumor growth and metastasis. MDSCs are one of the
immuosuppressive populations, which are rapidly attracting attention in
tumor biology [20]. MDSCs are a population of immature myeloid cells
(IMCs) and mature myeloid cells with immune suppressive activity. Under
physiological conditions, IMCs produced by bone marrow can differentiate
into mature granulocytes, monocytes and dendritic cells (DCs). In
pathological conditions, especially cancer, the differentiation of IMCs
is inhibited by molecules released by tumor cells, stromal cells and
activated immune cells, which leads to the accumulation of MDSCs
[21-23]. In human and mice, PMN-MDSCs and monocytic MDSCs (M-MDSCs)
are the two main subsets of MDSCs, in which PMN-MDSCs that account for
70-80% of total MDSCs are the prioritized population [24]. In tumor
microenvironment (TME), PMN-MDSCs are the main subset of MDSCs that
induce tumor immune escape. Besides PMN-MDSCs migrating from bone marrow
to TME, M-MDSCs and mature granulocytes in TME can also convert into
PMN-MDSCs to induce the immunosuppression more effectively [25].
PMN-MDSCs have previously been confirmed to be involved in the
progression of NSCLC by promoting tumor immune escape and metastasis in
both preclinical and clinical trails [26-28]. However, PMN-MDSCs,
which were initially identified as a population of terminally
differentiated neutrophils with immunosuppression, shared the similar
morphology and phenotype with mature ones. Therefore, it was the
suppressive activity, but not phenotype, was the most reliable approach
to distinguish PMN-MDSCs from neutrophils [20]. Recently, it was
confirmed that LOX-1 could be used to distinguish the population of
PMN-MDSCs in cancer patients. It was found that the newly defined
LOX-1+CD15+ PMN-MDSCs enhanced
immune suppression which promoted tumor progression [29-32]. Thus,
we attempted to ensure the application of
CD15+LOX-1+ PMN-MDSCs in NSCLC
diagnosis in present study, as well as identify their association with
NSCLC prognosis and recurrence after surgery.