Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma

Abstract

Recent clinical results for PD-1 blockade therapy have demonstrated durable tumor control with minimal immune-related adverse effects. PD-L1 is induced in non-lymphoid tissue cells and tumor cells, in addition to tissue-recruiting immune cells, under inflammatory conditions triggered by several cytokines, especially IFN-γ, and exogenous stimuli delivered by pathogen-associated molecular patterns. Receptor-mediated signaling molecules that affect the cell cycle, proliferation, apoptosis, and survival (including NF-κB, MAPK, PI3K, mTOR, and JAK/STAT) are involved in PD-L1 induction. PD-L1 expression in tumor cells is also triggered by the signals described above, but in some instances, intrinsic cell alteration associated with carcinogenesis contributes to PD-L1 induction. The tumor suppressor genes PTEN and Lkb1 and epithelial-mesenchymal transition-related molecules are also involved in the regulation of PD-L1 expression. Notably, squamous cell carcinoma of the head and neck (SCCHN) often exhibits both host immunosuppression and cytogenetic alternations of tumor cells. Precise understanding of how PD-L1 expression is controlled will allow the development of effective approaches to PD-1 blockade therapy for patients with SCCHN.

CD8+/FOXP3+ Ratio and PD-L1 Expression Associated With Survival in pT3N0M0 Stage Esophageal Squamous Cell Cancer

“…It might be related to the slightly worse hypoxia conditions in longer tumors, as PD-L1 is reportedly induced under hypoxia conditions [30,31]. Additionally, upstream molecules involved in PD-L1 expression may also promote cellular proliferation [27,32]. Another possible explanation is that activation of the PD-1/PD-L1 pathway may promote tumor immune escape, allowing tumor cells to proliferate and spread more rapidly [28].…”

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

“…Assays of PD-L1 protein expression by immunohistochemistry are used to determine which tumors would best be treated with an anti-PD-L1 antibody, but it is an imperfect measurement practice because there is lack of standardization of methods and it can sometimes be difficult to differentiate PD-L1-positive tumor cells from the other PD-L1-positive cells in the tumor microenvironment [73] . Moreover, immunohistochemistry has a lower sensitivity compared to studies measuring PD-L1 mRNA expression [74] . Anti-PD-1 and anti-PD-L1 antibody treatments are currently the most investigated ICIs because they have shown less severe toxicity, or high-grade "immunerelated adverse effects" (irAEs), than anti-CTLA-4 antibody treatments (5-20% compared to 10-40% respectively) [75][76][77][78][79] .…”

A Review of Cutaneous Squamous Cell Carcinoma Epidemiology, Diagnosis, and Management

“…Recent preclinical studies found programmed cell death protein 1 (PD-1) overexpression in keratinocytes to be associated with accelerated SCC development (74). Immunotherapeutic agents blocking PD-1/PD-1L1 (PD-1 ligand 1) pathway are currently undergoing phase II studies in patients with locally advanced or metastatic CSCC.…”