Role of Programmed Death Ligand-1 in Malignancies

Immunotherapy has recently emerged as the fourth pillar of cancer treatment, together with surgery, radiation, and chemotherapy. One of the most widely studied topics in the field of immunotherapy is the blockade of immune checkpoints out of which programmed cell death 1 has been studied in depth. PD-1 is a member of the B7 receptor family that modulates the T-cell response (2).

Importance of  Immune Checkpoint?

It is important for host cells to maintain immune homeostasis in order to survive.

Excessive immune response can lead to autoimmune diseases and lower levels of immune response can lead to infections and malignancies.

As we know that T cells are the major players in immune response, and as such they express multiple co inhibitory receptors such as Lymphocyte activation gene-3 (LAG-3), Programmed cell death protein-1 (PD-1), and cytotoxic  lymphocyte associated protein-4. These molecules act as immune checkpoints and modulate immune response to chronic infections, tumour and self proteins, showing the importance of immune checkpoint and that these checkpoints can be targeted to enhance anti-tumour activity.

What are B7 receptors?

B7 receptors are a family of cell surface protein ligands that bind to CD28 family on receptors, and regulate costimulatory or coinhibitory signals.

PDL1 is a ligand which binds to PD-1, which in turn causes T cell inhibition and down regulation of the T-cell response.

 Programmed cell death ligand 1 (B7-H1/CD274), an immune checkpoint molecule, is the ligand of PD-1(3). Activation of PD-1 causes T-cell inhibition through connecting with PD-1 ligands (PD-L1 and PD-L2), resulting in the down-regulation of the T-cell response (2,4).

Studies have shown that PD-L1 expression in various types of tumours have increased and this causes decreased T-cell activity enhancing tumour survival.

Prior to treatment PD-L1 expression was shown to be present in non-small cell lung cancer, ovarian clear cell carcinoma and renal cell carcinoma (2). 

PD-L1 expression can be promoted following chemotherapy and is a sign of poor prognosis in patients with non small cell lung carcinoma. (1). 

A study on endometrial carcinoma reported that in tumor cells 36.2% were PD-L1 positive and 64.4% were PD-L2 positive staining. There was a statistically significant association between the FIGO grade and the PD-L1 score (2). PD-L1 expression is also associated with epithelial to mesenchymal transition (EMT) process. 

What is epithelial to mesenchymal transition?

It is a process by which epithelial cells lose their cell polarity and cell-cell adhesion processes and gain migratory and invasive properties to become mesenchymal stem cells.

PD-L1 is frequently overexpressed in triple negative breast cancer(basal type)  which exhibits a relatively stronger stemness(property of stem cells distinguishing it from ordinary cells) and poor disease prognosis.

It was found that PD-L1 expression increase in breast cancer tissues and cells with adriamycin resistance, and enhanced the stemness of breast cancer cells via activating PI3K/Akt and ERK1/2 signaling (1). These effects suggest that PD-L1 might promote the stemness of breast cancer cells (1). 

A recent study also demonstrated that PDL-1 induces macrophage polarization and treatment with anti PD-1 antibody polarize the macrophage compartment towards a more pro-inflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression (4,5) 

Breaking the PD-1 and PDL1 bond

The anti-PD-1 antibodies nivolumab and pembrolizumab were recently approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer (NSCLC), and other malignant tumors. It has been shown that antibody therapies that break the PD-1 and PD-L1 interaction, namely, PD-1 (e.g. Pembrolizumab and Nivolumab) and PD-L1 (e.g. Atezolizumab and Avelumab) have antitumor effects on several tumors such as melanoma, non–small cell lung cancer, renal cell cancer, and Hodgkin lymphoma. The benefit of immune checkpoint inhibitor therapy has been observed in relation to several tumors. Pembrolizumab is one such treatment as it is a PD-1 inhibitory antibody that exhibits robust antitumor activity and an appropriate safety profile in multiple tumor types (1,2). 

Nevolumab Regimens

Clinically prescribed mostly in resistant or metastatic cases, some of the regimens used for Nevolumab are as follows:

  • Melanoma– 240 mg once every two weeks, or 480 mg once every 4 weeks
  • In non-small cell cancer of lung with EGFR and ALK mutations, who have shown progression on FDA approved therapy, 240 mg once every two weeks
  • In small cell lung cancer

240 mg once every two weeks

  • In advanced renal cell carcinoma– In those patient who have received prior anti-angiogenic therapy-

240 mg once every two weeks, or 480 mg once every 4 weeks

  • Hepatocellular carcinoma– those who have been previously treated with sorafinib:

 240 mg once every two weeks, or 480 mg once every 4 weeks

  • Head and neck cancers(metastatic squamous cell)-patients who have progressed on platinum based therapy:

240 mg once every two weeks, or 480 mg once every 4 weeks

What are ALK and EGFR mutations?

ALK mutations are rearrangement of the ALK gene on chromosome 2, increases the risk of developing cancers and drug resistance.

Epidermal growth factor receptor(EGFR) is a transmembrane protein with cytoplasmic kinase activity, extending through the cell membrane and is an important component in growth factor signalling from extracellular milieu to the cell. EGFR mutations are rearrangements in those genes which contain the ‘recipe’ for the EGFR protein.

The Nobel prize for physiology in 2018 was won for targeted therapy towards PD-1 (nivolumab,pembrolizumab) and PD-L1(atezolizumab, durvalumab). PD-1 and PD-L1 blockade therapy may be a major form of cancer immunotherapy methods in the future and opens a new era of cancer treatment. With a deeper understanding of genetic information a lot of effort is being put into PD-1 blockade alone or in combination with blockade of other targets to acheive clinical results.

1. Peng H, Li Z, Fu J, Zhou R. <p>Growth and differentiation factor 15 regulates PD-L1 expression in glioblastoma</p>. Cancer Management and Research. 2019;Volume 11:2653-2661. 
2. Sungu N, Yildirim M, Desdicioglu R, Başaran Aydoğdu Ö, Kiliçarslan A, Tatli Doğan H et al. Expression of Immunomodulatory Molecules PD-1, PD-L1, and PD-L2, and their Relationship With Clinicopathologic Characteristics in Endometrial Cancer. International Journal of Gynecological Pathology. 2019;38(5):404-413. 
3.	Gao L, Guo Q, Li X, Yang X, Ni H, Wang T et al. MiR-873/PD-L1 axis regulates the stemness of breast cancer cells. EBioMedicine. 2019;41:395-407. 
4.	Chen W, Wang J, Jia L, Liu J, Tian Y. Attenuation of the programmed cell death-1 pathway increases the M1 polarization of macrophages induced by zymosan. Cell Death & Disease. 2016;7(2):e2115-e2115.
5. Xiong H, Mittman S, Rodriguez R, Moskalenko M, Pacheco-Sanchez P, Yang Y et al. Anti–PD-L1 Treatment Results in Functional Remodeling of the Macrophage Compartment. Cancer Research. 2019;79(7):1493-1506.

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