PD-L1-Mediated Immunosuppression in Oral Squamous Cell Carcinoma: Relationship With Macrophage Infiltration and Epithelial to Mesenchymal Transition Markers

Abstract

To date, immune check-point inhibitors (ICIs), particularly inhibitors of programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) have become prominent in cancer treatment and also improved life expectancy of cancer patients. As key regulators of PD-1/PD-L1 axis, the recruitment of tumor-associated macrophages (TAMs) enhances aggressive and invasive properties of tumors in immunosuppressive tumor microenvironment (TME) and promotes epithelial-mesenchymal transition (EMT). The aims of the study were first to characterize the critical links among PD-L1, TME and EMT process and, further, to explore the sensitivity of different chemical agents to different PD-L1 expression groups. Bioinformatical analysis revealed that PD-L1 was highly expressed in OSCC and higher PD-L1 expression correlated with worse survival in patients. Notably, PD-L1 was positively correlated with macrophages infiltration and EMT markers gene expression. Moreover, patients in the PD-L1high group were at a significant chance of benefiting from ICI treatment and they also showed higher sensitivity to the chemical drugs (olaparib, paclitaxel, docetaxel, and pazopanib). These findings implicate PD-L1 could serve as a novel target for prognostic and therapeutic approaches in OSCC patients; PD-L1-mediated immune evasion might be attributable to the infiltration of macrophages, resulting EMT progress; Chemical agents in combination with PD-L1 inhibitor could be served as personalized treatment plan for OSCC patients so as to maximize patient benefit.

The role of long noncoding RNAs as regulators of the epithelial–Mesenchymal transition process in oral squamous cell carcinoma cells

“…In patients with high-grade invasive OSCC, programmed-death 1 (PD-1) receptor/programmed-death ligand (PD-L1) overexpression has been seen in macrophages and dendritic cells. Similar findings have been observed for mesenchymal OSCC cells in vitro ( Hirai et al, 2017 ; Wu et al, 2021 ). Tumor-associated macrophages (TAMs) with an M1 phenotype can drive EMT progression and promote cancer-stem cell (CSC) development in OSCC through the upregulation of MMP-14 and MME ( You et al, 2022 ).…”

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

“…PD-L1 on cancer cells' surface enables them to inhibit T-cell activation, while simultaneously causing them to be exhausted, eventually preventing cancer cells from being targeted by activated T cells (2). High PD-L1 has been exhibited in circulating tumor cells as well across cancers (54,55), and EMT has been associated with higher PD-L1 levels (5,(56)(57)(58)(59). Here, we have investigated PD-L1 levels in hybrid E/M phenotypes, given their higher fitness for metastasis and evasion of various treatment options.…”

PD‐L1 in oral squamous cell carcinoma: A key biomarker from the laboratory to the bedside

“…Recently, the important oncology concept referred to as hyperprogressive disease (HD) was introduced, based on the observation of different response patterns to immunotherapy during cancer treatment (specifically, rapid tumor progression after the initiation of immunotherapy) (Kim et al, 2019 ). HD has been observed across various types of cancers, including OSCC, and has been associated with poor survival (Kim et al, 2019 ). Of note, IHC positivity for PD‐L1 is inversely correlated with HD, further highlighting the importance of striving for a standardized assessment of this biomarker.…”

“…The full text of potentially eligible articles was retrieved and evaluated by two authors to verify inclusion criteria and the quality of these studies. By applying the inclusion criteria, 12 studies were selected (Table 1 ) (Cho et al, 2011 ; de Vicente et al, 2019 ; Kogashiwa et al, 2017 ; Lenouvel et al, 2021 ; Mattox et al, 2017 ; Oliveira‐Costa et al, 2015 ; Pang et al, 2021 ; Quan et al, 2020 ; Satgunaseelan et al, 2016 ; Shen et al, 2021 ; Straub et al, 2016 ; Wu et al, 2021 ). Data extracted included: country and authors of each study, number of patients, clone of PD‐L1 used, cut‐off for positivity applied, and the HR for OS and DFS reported in the study.…”