Abstract
Immune checkpoint inhibitors that block the PD-1/PD-L1 signaling pathway have been used to treat a wide variety of cancers. Although results have been promising, significant inter-individual and inter-tumor variability has been observed. It is believed that better clinical outcome could be achieved if the treatment was individually designed based on the functional status of the PD-1/PD-L1 signaling and the cellular immunity. In this study, we analyzed the mRNA expression of PD-1 and other immunomodulatory genes in peripheral blood from cancer patients, and immunomodulatory gene expression during radiotherapy and immunomodulation therapy with cytokines. Our results show that the PD-1 mRNA expression is significantly increased in peripheral blood in cancer patients. Anti-cancer treatments can significantly modulate the PD-1 expression, but this is largely dependent on the initial immune status. Moreover, the PD-1 expression on peripheral lymphocytes can be immunoactivation-derived. These results suggest that the regulation and expression pattern of PD-1/PD-L1 signal is complicated which will influence the effect of blockade of the PD-1/PD-L1 signaling pathway for cancer treatment. Through combined analysis of PD-1, CTLA-4, and other immune markers in peripheral blood, we may accurately evaluate the functional status of PD-1/PD-L1 signaling and cellular immunity, thereby providing clues for guiding anti-PD-1 or anti-PD-L1 treatment.
Highlights
Programmed death-1(PD-1,CD279), a member of the immunoglobulin superfamily, is an immune checkpoint receptor that is expressed on the surface of peripheral T cells, B cells, natural killer T (NKT) cells, dendritic cells(DC), and some monocytes
Gene expression of PD-1 as well as cytotoxic T-lymphocyte antigen-4 (CTLA-4), CD25, CD28, Foxp3, TGF-β and IL-10 was increased in most cancer patients compared to that in healthy adults
No significant difference in PD-1 and CTLA-4 mRNA expression and in lymphocyte counts were observed between 7 lung cancer patients and 18 other malignancies in the immunomodulation therapy cohort, suggesting dysregulated cellular immunity in cancer patients
Summary
Programmed death-1(PD-1,CD279), a member of the immunoglobulin superfamily, is an immune checkpoint receptor that is expressed on the surface of peripheral T cells, B cells, natural killer T (NKT) cells, dendritic cells(DC), and some monocytes. Upon binding to its ligands, programmed death-1 receptor ligand-1 (PD-L1) or -2 (PD-L2), the PD-1 engagement leads to inhibition of cell growth and cytokine secretion, normally serving as a feedback inhibitory mechanism of the immune system [1,2,3,4,5,6]. This mechanism has been linked to immune tolerance and provides a possible mechanism of escaping immune surveillance when tumor cells become capable of expressing PD-L1 [7, 8]. A significant interindividual and inter-tumor variability in response to these antibodies has been observed [16]
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