Elevated Expression of Programmed Death-1 and Programmed Death Ligand-1 Negatively Regulates Immune Response against Cervical Cancer Cells

Abstract

The present study is to measure the expression of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), as well as its clinical significance in cervical cancer patients. Our results showed that different T cell subsets in patients with cervical cancer had high expression of PD-1, and DCs had high expression of PD-L1. High expression of PD-1 on Treg cells in cervical cancer patients facilitated the production of TGF-β and IL-10 but inhibited the production of IFN-γ. Cervical cancer elevated the expression of PD-1 and PD-L1 in mRNA level. PD-1 expression in peripheral blood of cervical cancer patients was related with tumor differentiation, lymph node metastasis, and invasiveness. PD-1/PD-L1 pathway inhibited lymphocyte proliferation but enhanced the secretion of IL-10 and TGF-β in vitro. In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer. Therefore, PD-1/PD-L1 pathway may become an immunotherapy target in the future.

Immune Regulatory Network in Cervical Cancer Development: The Expanding Role of Innate Immunity Mechanisms

“…Finally, there is one more important source of PD-L1 among adaptive immune cells represented by regulatory T cells (Treg); a correlation between PD-L1 expression and FoxP3+Treg was reported by Ma et al [75]. Moreover, CD4CD25 Tregs are able to upregulate PD-1 expression in patients with CIN/ cervical carcinoma [36], which, however, does not result in Treg exhaustion, but, conversely, favors upregulation of their immunosuppressive activity. Lastly, it has been reported that regional lymph nodes from stage IB1 cervical cancer patients, along with elevated PD-1, have increased expression of FoxP3 Treg-marker, which may shed light on the establishment of pre-metastatic niches [71], as well as on systemic expansion of suppressive mechanisms Tregs are engaged in.…”

“…Interestingly, according to Swangphon et al, cervical cancer patients exhibit altered ratio of M1/M2-polarized (CD64+/CD163+) monocytes not only at the local level, but in systemic circulation as well; notably, circulating M1/M2 ratio was shown to be correlated with the number of stroma-or peritumoral area-infiltrating M2-macrophages (CD163+), and with severity of the disease [35]. Similarly, cervical cancer patients displayed increased numbers of circulating dendritic cells (CD11b+) expressing PD-1L [36]. Moreover, an increase in the number of tumor-promoting M2-macrophages/ monocytes has been found to occur not only locally,…”

“…Regarding cervical cancer, one can observe an avalanche of new data emerged in recent 2 years on the expression of immune checkpoint markers, first of all PD-1/PD-1L, a hallmark of T cell exhaustion caused by chronic antigenic stimulation [66], as well as other members of B7 and CD28 protein families (e.g., B7-H3 [67] and B7-H4 [68]). For example, patients with CIN or cervical cancer show increased expression of PD-1 both in infiltrating lymphocytes and macrophages (TAMs) [69,70], as well as in circulating CD4 and CD8 T cells [36], and, furthermore, in the sentinel lymph nodes [71]. Cervical neoplastic cells are considered as the primary source of PD-1 Ligand (PD-1L) [69,70], with HPV16-Е7 oncoprotein proved to be the driving force for elevated PD-L1 expression [72] and copy number gains of PD-L1 gene being one of the putative underlying reasons [73,74].…”

Role of Immunotherapy in the Management of Locally Advanced and Recurrent/Metastatic Cervical Cancer

“…36 PD-L1+ immune cells were in greater abundance surrounding metastatic lymph nodes, consistent with reports that advanced disease has higher levels of PD-L1 expression. 36,37 Ionizing Radiation, the Immune System, and the Abscopal Effect…”

The expression of selected molecular markers of immune tolerance in psoriatic patients

“…The co-expression of the PD-1 with its ligand 1 (PD-L1) on Tregs enhances their proliferation and favors the maintenance of self-tolerance. 5 Human leukocyte antigen G, a nonclassical human leukocyte antigen (HLA), known as a tolerogenic molecule, is capable of downregulating the natural killer (NK) cells' cytotoxic activity, the inhibition of T cell migration, the induction of the apoptosis of activated CD8+ T cells, and the prevention of DC maturation. It induces the functional silencing of the immune response, which is indispensable in certain physiological settings, e.g., during pregnancy, but it also allows the tumor cells to escape the host's immune system.…”