PD-L1 in Pancreatic Ductal Adenocarcinoma: Comparison
Please note this is a comparison between Version 1 by Jianqiong Zhang and Version 2 by Conner Chen.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5–10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors. 

  • pancreatic ductal adenocarcinoma
  • immune checkpoint
  • cancer immunotherapy
  • PD-L1

1. Introduction

Despite the advancements in conventional systemic therapy, pancreatic ductal adenocarcinoma (PDAC)PDAC is one of the most aggressive cancers, with a 5-year survival rate approaching 5–10% in 2020 [1][2][1,2]. In 2021, it became the third leading cause of cancer-related mortality and is projected to overtake lung cancer as the second leading cause by 2030 [3]. Since most patients (80–85%) have locally advanced or metastatic cancer at first diagnosis, conventional chemotherapy based on drugs such as fluorouracil and gemcitabine remain the main treatment for patients with PDAC. Metastatic PDAC has a median overall survival (OS) of less than a year, and locally-progressing unresectable PDAC is only marginally better [4][5][4,5].
PDAC patients account for over 90% of all cases of pancreatic cancer. The majority of PDAC originate from pancreatic intraepithelial neoplasias, which advance through the acquisition of genetic changes and culminate in the formation of overt PDAC. A minority of PDAC arises from cystic neoplasms [4]. PDAC is characterized histologically by a severely desmoplastic tumor microenvironment (TME), which comprises around 70% of tumor tissue. This fibrotic milieu is produced by cancer-associated fibroblasts (CAFs) [6]. The TME of PDAC consists of immune cells, CAFs, neurons, vessels, and extracellular matrix components such as collagen, fibronectin, and hyaluronic acid [7].
Over the past decade, inhibiting the PD-L1/PD-1 pathway has shown promising results. Although good clinical responses have been achieved in some solid and hematologic tumors, such as melanoma and non-small cell lung cancer (NSCLC), PDAC is mostly resistant to immunotherapies [8]. The profoundly immunosuppressive TME of PDAC should be primarily responsible for this outcome, as regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and numerous M2 tumor-associated macrophages (TAM) infiltrate the TME and inhibit the migration and activation of T cells [6][9][6,9]. In addition to the regulatory immunological signature, an effector immune infiltrate, including CD3, CD4, and CD8 T cells, is also present in PDAC [10][11][10,11]. The B7 family is an immunoglobulin superfamily, and secondary signaling for T cell activation is dependent on the B7 family. Immune checkpoints of the B7 family play a key role in regulating the critical bidirectional signals that drive T cell activation and self-tolerance. The B7 family can produce positive signals to initiate and sustain T cell activity as well as negative signals to regulate and inhibit T cell responses. Ultimately, the T cell immune response is determined by the equilibrium between co-stimulatory and co-inhibitory signals [12][13][12,13]. The T cells that infiltrate the TME of PDAC interact with tumor cells (TCs) and immunosuppressive cells, exhibiting an “exhausted” phenotype. When the PD-1/PD-L1 pathway is disrupted, clinical trials show no clinical effect on PDAC, indicating that T cells’ anti-tumor function cannot be restored. This disappointing result demonstrates the urgent need to discover more novel immune checkpoints in the TME of PDAC [14][15][14,15].
The B7 family members have attracted much attention due to their crucial roles in immune evasion and tumorigenesis, and a variety of preclinical and clinical treatments have been established based on them. To date, the B7 family consists of 11 members: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), PD-L2 (PDCD1LG2, B7-DC, CD273), B7-H2 (CD275, ICOS-L, B7RP1), B7-H3 (CD276), B7-H4 (B7x, Vtcn1, B7S1), VISTA (B7-H5, GI24, DD1α, SISP1), B7-H6 (NCR3LG1), HHLA2 (B7-H7), and ILDR2 [13]. It has been shown that some B7 family members receive multiple signaling pathways and are widely expressed on a variety of different cell surfaces in the TME of PDAC. Some molecules belonging to the B7 family in the TME of PDAC have been proven to not only regulate the activation or suppression signals of immune cells but also participate in tumor development, invasion, drug resistance, and epithelial-mesenchymal transition (EMT) independent of their immune functions [12][16][17][18][19][12,16,17,18,19].

2. PD-L1

This programmed cell death ligand 1 (PD-L1), which belongs to the B7 family, is a ligand for PD-1 found in a variety of tumors. A high expression level of PD-L1 is found primarily in TCs but can also be found in epithelial cells, macrophages, dendritic cells, lymphocytes, etc., in the TME of PDAC [20][21][20,21]. PD-1 is predominantly expressed in activated lymphocytes. The PD-1 and PD-L1 signaling pathways can suppress the activation of immune cells and induce T cell apoptosis, leading to the exhaustion of activated immune cells and promoting the infiltration of Tregs [22]. Soluble PD-L1, which is a type of PD-L1, is detected in the blood of some patients with PDAC and has predictive significance [23][24][23,24]. Multiple studies have demonstrated the association between a high expression level of PD-L1 in patients with PDAC and a poor prognosis [21][22][24][21,22,24]. Immune checkpoint monoclonal antibody (mAb) inhibitors targeting PD-1/PD-L1 have achieved higher objective response rates (ORR) with very few adverse events in patients with hematological tumors and numerous solid tumors, such as NSCLC, gastric cancer, and melanoma, by disrupting the immunosuppressive microenvironment and reactivating T cells [8][25][26][8,25,26]. However, the benefit of PD-1/PD-L1 inhibitors alone in patients with PDAC is limited due to the complex TME, which exhibits an immunosuppressive immune “desert” phenotype [27]. In a phase I multicenter study in 2012 that included 207 cancer patients to receive an anti-PD-L1 antibody, no objective response was observed in 14 patients with PDAC [28]. To overcome resistance to PD-1/PD-L1 inhibitors and combine different anti-tumor treatment mechanisms, clinical researchers are combining PD-1/PD-L1 inhibitors with chemotherapy, radiotherapy, targeted therapy, or other immunotherapies [28]. Multiple therapeutic strategies that are being evaluated are summarized in Table 1.
Table 1.
Ongoing clinical trials targeting B7 family members in PDAC.
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