Introduction
Programmed death-ligand 1 (PD-L1) is a protein that is highly expressed on the surface of many cancer cells. As PD-L1’s receptor, PD-1 belongs to the immunoglobulin superfamily and can bind to both PD-L1 and PD-L2. The binding between PD-L1 and PD-1 on the surface of the tumor-infiltrating lymphocytes leads to immune escape of tumors and immunosuppression.
PD-L1 function
PD-L1 is expressed on many cells, such as T cells and B cells. PD-L2 is mainly expressed on dendritic cells and monocytes. The difference in the distribution of PD-Ls can help us explain their different roles in immune regulation: PD-L1 is widely distributed in tissues and binds to PD-1 to prevent autoimmunity by inhibiting T and B cell activities, while PD-L2 is mainly involved in the regulation of immune responses caused by natural environmental antigens.
Figure 1 Transcriptional activation of PD-L1 in response to different signaling pathways (Wang et al 2018)
PD-L1 and tumor
In the tumor microenvironment, tumor-associated macrophages (TAM) can promote tumor progression and metastasis, and participates in tumor immunity. On the one hand, TAM secretes vascular endothelial growth factor VEGF, IL-1β, TNF, and IL-10 to attract regulatory T cells (Tregs), promote PD-L1 expression on the surface of tumor cells, inhibit the function of effector T cells, and mediate the invasion and metastasis of tumor cells to distant regions. One study found that 65.3% of the 136 patients with non-small cell lung cancer had positive PD-L1 expression, shown by immunochemical staining. Both TAM and PD-L1 were negatively correlated with lymph node metastasis. Both PD-1 and Treg cells were involved in the distant metastasis of tumors, and high levels of PD-1 enhanced the inhibitory function of Treg cells. Some lymphocyte chemotactic factors such as CCL2, CXCR2, and CXCL5 can increase the expression level of PD-L1, induce the occurrence of EMT, and promote tumor invasion and metastasis.
Clinical application of PD-L1
Atezolizumab is the first FDA-approved anti-PD-L1 immunotherapy for bladder cancer and metastatic non-small cell lung cancer. In a Phase II clinical trial for cisplatin-treated advanced or metastatic urothelial cancer, Atezolizumab treatment was shown to reduce tumor volume in 15% of patients. Tumor volume was also reduced in 26% of patients with high PD-L1 expression after treated with Atezolizumab.
At the same time, Tezolizumab can be used as an alternative to cisplatin in advanced urothelial carcinoma. Recently, Roche announced the result of phase III clinical trial. The median survival of patients with metastatic lung cancer treated with Atezolizumab was 4.2 months longer than that of the chemotherapy drug docetaxel. However, the results of this trial were not related to the difference in PD-L1 expression levels in patients. This indicates that PD-L1 cannot be used as a specific molecular marker for prognostic efficacy judgment, and it is not the only factor affecting the therapeutic effect of Atezolizumab on metastatic tumors. Some related factors could be tumor type, presence of tumor infiltrating cells (TIL), and other inhibitory pathways. Other PD-L1 inhibitors include Durvalumab (Imfinzi), MPDL3280A, BMS-936559, MSB0010718C, etc.
References
1.Iraolagoitia, X. L. R. , Spallanzani, R. G. , Torres, N. I. , Araya, R. E. , Ziblat, A. , & Domaica, C. I. , et al. (2016). Nk cells restrain spontaneous antitumor cd8+ t cell priming through pd-1/pd-l1 interactions with dendritic cells. The Journal of Immunology, jimmunol.1502291.
2. Zak, K. M. , Grudnik, P. , Guzik, K. , Zieba, B. J. , Musielak, B. , & Dömling, Alexander, et al. (2016). Structural basis for small molecule targeting of the programmed death ligand 1 (pd-l1). Oncotarget, 7(21).
3. Wang, Y. , Wang, H. , Yao, H. , Li, C. , & Xu, J. . (2018). Regulation of pd-l1: emerging routes for targeting tumor immune evasion. Frontiers in Pharmacology, 9.