PD-L1

Introduction

The receptor for PD-L1 is PD-1, which belongs to the immunoglobulin superfamily and can bind to PD-L1 and PD-L2, respectively, and is their common receptor. PD-L1 is highly expressed on the surface of many tumor cells, and it is one of the important reasons leading to immune escape of tumor by binding to PD-1 molecule on the surface of tumor-infiltrating lymphocytes and inhibiting the function of lymphocytes.

PD-L1 function

PD-L1 is expressed in T cells, B cells, etc. PD-L2 is mainly expressed in dendritic cells, monocytes, etc. The difference in the distribution of PD-L can help us explain their different roles in the regulation of immune function: PD-L1 is widely distributed in tissues and binds to PD-1 to prevent autoimmunity by inhibiting T and B cell activities. The occurrence of disease, while PD-L2 is mainly involved in the regulation of immune responses caused by natural environmental antigens. The difference in the distribution of PD-L can help us explain their different roles in the regulation of immune function: PD-L1 is widely distributed in tissues and binds to PD-1 to prevent autoimmunity by inhibiting T and B cell activities. The occurrence of disease, 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 invasion and metastasis, and are important participants in tumor immune effects. On the one hand, vascular endothelial growth factor VEGF, IL-1β, TNF, IL-10 secreted by TAM can attract Tregs and promote the expression of PD-L1 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. In non-small cell lung cancer, immunohistochemical staining revealed that 65.3% of the 136 patients had positive PD-L1 expression, and both TAM and PD-L1 were negatively correlated with lymph node metastasis. Both PD-1 and Treg cells are involved in the distant metastasis of tumors, and high levels of PD-1 can enhance 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 the invasion and metastasis of cancer.

Clinical application of PD-L1

Atezolizumab is the first FDA-approved anti-PD-L1 immunotherapeutic for immunotherapy of bladder cancer and metastatic non-small cell lung cancer. In a Phase II clinical trial of cisplatin-treated advanced or metastatic urothelial cancer, the results showed that Atezolizumab treatment reduced tumor volume in 15% of patients. In patients with high PD-L1 expression, Atezolizumab treatment reduced tumor volume in 26% of patients.

At the same time, Tezolizumab can be used as an alternative to cisplatin in advanced urothelial carcinoma. Recently, Roche announced the results of a 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 the immunotherapeutic drug Atezolizumab on metastatic tumors, which may be related to tumor type, presence of tumor infiltrating cells (TIL) and other inhibitory pathways. In addition, antibodies related to PD-L1 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.