PD-L1 Positive: Impact on Immune Cell Behavior

PD-L1 (programmed death-ligand 1) plays a key role in immune regulation by interacting with the PD-1 receptor on T cells. This interaction helps maintain immune tolerance but can also be exploited by diseases like cancer to evade immune responses. Understanding how PD-L1 expression influences immune cell behavior is crucial for developing targeted therapies, particularly in immuno-oncology.

Research has shown that PD-L1 affects immune function in both normal and pathological conditions. Its impact on T-cell activity, along with its detection methods and tissue-specific distribution, provides valuable insights into its broader role in immunity.

Expression In Normal Immune Cells

PD-L1 expression in immune cells is tightly regulated, varying by cell type, activation state, and environmental signals. Under baseline conditions, it is expressed at low levels on antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells. Inflammatory signals, particularly interferons like IFN-γ, significantly upregulate PD-L1, reinforcing its role in immune modulation.

Macrophages display dynamic PD-L1 expression depending on their polarization state. M1 macrophages, associated with pro-inflammatory responses, express lower PD-L1 levels than M2 macrophages, which are linked to immune suppression. This differential expression suggests PD-L1 helps regulate macrophage function, either promoting or dampening immune activity. Neutrophils can transiently express PD-L1 upon activation, particularly in response to bacterial infections or cytokine stimulation, indicating a role in acute immune regulation.

B cells express PD-L1, particularly in germinal centers where they interact with T follicular helper cells, influencing antibody production. Regulatory B cells (Bregs), known for their immunosuppressive properties, exhibit higher PD-L1 levels, contributing to T-cell modulation and immune homeostasis.

T cells also express PD-L1, though at lower levels than APCs. Activated CD4+ and CD8+ T cells may transiently upregulate PD-L1, particularly in chronic antigen exposure scenarios, such as persistent viral infections. This expression has been linked to T-cell exhaustion, though its precise functional role remains an area of active investigation.

Patterns In Pathological Conditions

PD-L1 expression is dysregulated in various diseases, often contributing to disease progression by altering cellular interactions. In cancer, malignant cells exploit PD-L1 upregulation to evade immune detection. This phenomenon has been documented in tumors such as non-small cell lung cancer (NSCLC), melanoma, and triple-negative breast cancer, where PD-L1 positivity correlates with poorer prognosis. Genomic aberrations, including amplification of the PD-L1 gene locus on chromosome 9p24.1, and oncogenic pathways like PI3K/AKT and JAK/STAT contribute to its overexpression.

Chronic infections also induce sustained PD-L1 expression on immune and non-immune cells. Viral infections like HIV, hepatitis B, and hepatitis C are associated with elevated PD-L1 levels, particularly on monocytes and dendritic cells, due to prolonged exposure to inflammatory cytokines like IFN-γ and IL-10. In tuberculosis, Mycobacterium tuberculosis infection heightens PD-L1 expression on macrophages, impairing bacterial clearance. Sepsis triggers widespread PD-L1 upregulation on circulating leukocytes, correlating with immune paralysis and increased susceptibility to secondary infections.

Autoimmune diseases show varying PD-L1 alterations. In systemic lupus erythematosus (SLE), reduced PD-L1 expression on APCs may contribute to heightened autoreactive T-cell activation. In contrast, rheumatoid arthritis displays increased PD-L1 levels in inflamed joints, suggesting both protective and pathogenic roles. In multiple sclerosis, elevated PD-L1 expression on microglia has been linked to disease progression, potentially contributing to T-cell exhaustion within the central nervous system.

Mechanisms Affecting T-Cell Responses

PD-L1 modulates T-cell function by interacting with the PD-1 receptor, inhibiting activation, proliferation, and survival. Upon binding to PD-1, PD-L1 recruits phosphatases SHP-1 and SHP-2, which dephosphorylate key signaling molecules like CD3ζ, ZAP-70, and PI3K, reducing cytokine production and limiting T-cell expansion.

PD-L1 engagement also alters T-cell metabolism, inhibiting glycolysis while promoting fatty acid oxidation, shifting T cells toward a quiescent state. This metabolic shift leads to progressive loss of mitochondrial integrity and bioenergetic capacity, particularly in chronic antigen exposure. T cells subjected to prolonged PD-L1-mediated inhibition exhibit reduced expression of transcription factors like T-bet and Eomes, leading to exhaustion characterized by impaired cytotoxicity and diminished responsiveness to stimulation.

PD-L1 also influences co-stimulatory and co-inhibitory pathways. It reduces CD28 expression, limiting activation signals and reinforcing functional impairment. Additionally, PD-L1 signaling enhances inhibitory receptors like TIM-3 and LAG-3, which further suppress T-cell function. This layered regulatory network progressively dampens immune responses, especially in persistent antigen exposure environments.

Laboratory Techniques To Identify Positive Expression

PD-L1 detection relies on immunohistochemistry (IHC), molecular assays, and flow cytometry. IHC is the most widely used method for assessing PD-L1 in tissues, particularly in oncology. FDA-approved assays such as 22C3, 28-8, SP142, and SP263 determine PD-L1 status in tumor biopsies, with expression quantified using tumor proportion scores (TPS) or combined positive scores (CPS). However, variability in staining protocols and antibody clones necessitates careful validation.

Flow cytometry allows precise quantification of PD-L1 on individual cell populations in blood or dissociated tissues, distinguishing between immune cell subsets. Multiparametric panels incorporating fluorochrome-conjugated antibodies enable simultaneous assessment of co-expressed markers. While effective for high-throughput analysis, flow cytometry requires fresh or cryopreserved samples, limiting its use for archived tissues.

In situ hybridization (ISH), such as RNA Scope, complements protein-level detection by assessing PD-L1 mRNA expression within tissue architecture. Digital pathology and AI-driven image analysis are increasingly integrated into PD-L1 assessment, improving reproducibility and minimizing variability.

Tissue-Specific Prevalence

PD-L1 expression varies across tissues, influenced by physiological and pathological factors. In healthy tissues, baseline expression is low but can be upregulated by local immune activation. Organs with high immune surveillance, such as the lungs, liver, and intestines, exhibit greater inducibility due to constant antigen exposure. Alveolar epithelial cells in the lungs transiently express PD-L1 in response to infections, regulating immune responses to airborne pathogens. Hepatocytes and Kupffer cells in the liver upregulate PD-L1 in conditions like viral hepatitis, modulating inflammation and preventing excessive immune-mediated damage.

In tumors, PD-L1 distribution is heterogeneous, reflecting interactions between tumor-intrinsic factors and immune infiltration. Cancers like NSCLC and urothelial carcinoma frequently exhibit PD-L1 positivity on both tumor and immune cells, contributing to immune evasion. In contrast, glioblastoma and pancreatic adenocarcinoma show more restricted PD-L1 expression, often localized to tumor-associated macrophages rather than tumor cells. The spatial organization of PD-L1 also influences response to checkpoint inhibitors, as diffuse expression across malignant and stromal compartments may affect therapeutic outcomes differently than focal PD-L1 positivity. Advanced imaging techniques, including multiplex immunofluorescence and spatial transcriptomics, are enhancing understanding of PD-L1 distribution in disease contexts.