PD-L1 Lung Cancer: Mechanisms Driving Tumor-Immune Evasion

Lung cancer remains a leading cause of cancer-related deaths, with immune evasion playing a critical role in its progression. A key mechanism involves programmed death-ligand 1 (PD-L1), which helps tumors escape immune surveillance by suppressing T-cell activity. Understanding PD-L1’s role in immune evasion is essential for improving therapeutic strategies.

Immune checkpoint inhibitors targeting PD-L1 have been developed, but patient responses vary. Identifying the factors regulating PD-L1 expression and its interactions within the tumor microenvironment can refine treatment approaches.

Role Of PD-L1 In Tumor-Immune Interactions

PD-L1, a transmembrane protein expressed on tumor and immune cells, binds to its receptor, programmed death-1 (PD-1), on T cells. This interaction transmits an inhibitory signal that dampens T-cell activation, reducing cytokine production and impairing cytotoxic responses. By exploiting this pathway, lung tumors create an immunosuppressive environment that allows malignant cells to proliferate unchecked.

PD-L1 expression in the tumor microenvironment varies, influenced by tumor properties and immune pressures. Some lung tumors exhibit constitutive PD-L1 expression due to oncogenic signaling pathways, such as EGFR mutations or ALK rearrangements. Others upregulate PD-L1 in response to inflammatory cytokines like interferon-gamma (IFN-γ), enabling tumors to evade immune attack by co-opting the immune system’s own mechanisms.

Beyond immune suppression, PD-L1 contributes to tumor survival through non-immune mechanisms. It promotes epithelial-to-mesenchymal transition (EMT), enhancing invasiveness and metastatic potential. PD-L1 also confers resistance to apoptosis, allowing cancer cells to persist despite hostile conditions. These tumor-intrinsic functions reinforce its role in lung cancer progression, making it a central therapeutic target.

Mechanisms Influencing PD-L1 Expression

PD-L1 expression in lung cancer is shaped by genetic alterations, signaling cascades, and microenvironmental factors. Oncogenic mutations in pathways such as EGFR, ALK, and KRAS influence transcriptional and post-translational control. EGFR mutations elevate PD-L1 levels via PI3K/AKT and JAK/STAT signaling, while ALK rearrangements upregulate PD-L1 through STAT3 activation.

Epigenetic modifications also regulate PD-L1 by altering chromatin accessibility and transcriptional activity. DNA methylation and histone modifications can suppress or enhance PD-L1 transcription. Research in Nature Communications has linked demethylation of the PD-L1 promoter to increased gene expression in certain lung cancer subtypes. Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), modulate PD-L1 levels by affecting mRNA stability and translation efficiency. For example, miR-200 negatively regulates PD-L1, while lncRNAs such as MALAT1 contribute to its upregulation.

Extracellular signals within the tumor microenvironment further influence PD-L1 expression. Hypoxia induces PD-L1 via hypoxia-inducible factor-1 alpha (HIF-1α), as reported in Cancer Research. Under low oxygen conditions, HIF-1α binds to hypoxia response elements in the PD-L1 promoter, increasing transcription. Metabolic reprogramming also plays a role, with elevated lactate levels and altered glucose metabolism contributing to PD-L1 expression. Studies in Cell Metabolism suggest glycolytic tumors exhibit higher PD-L1 levels due to metabolic crosstalk between cancer cells and stromal components.

Expression Patterns In Different Lung Cancer Subtypes

PD-L1 expression varies across lung cancer subtypes, reflecting their molecular and histopathological differences. Non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancer cases, shows heterogeneity in PD-L1 levels based on histology and genetic alterations. Adenocarcinomas, the most common NSCLC subtype, exhibit a wide spectrum of PD-L1 expression, often higher in tumors with KRAS mutations due to inflammatory gene signatures. In contrast, adenocarcinomas with EGFR mutations show more variable PD-L1 expression.

Squamous cell carcinoma (SCC), another major NSCLC subtype, tends to exhibit higher PD-L1 expression than adenocarcinoma. This may be attributed to the inflammatory and smoking-associated mutational landscape of SCC, which promotes a tumor microenvironment favoring PD-L1 upregulation. Frequent alterations in PI3K/AKT and JAK/STAT pathways contribute to increased PD-L1 transcription in SCC.

Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, generally exhibits low PD-L1 expression. Despite rapid proliferation and genomic instability, most SCLC tumors do not upregulate PD-L1. However, a subset of SCLC cases with high tumor mutational burden or specific genomic alterations, such as MYC amplification, display elevated PD-L1, suggesting molecular subtypes that warrant further investigation.

Immune Checkpoint Interactions

PD-L1 interacts with other immune checkpoint molecules, shaping lung cancer’s immunosuppressive landscape. While PD-L1 primarily inhibits immune activation by binding to PD-1 on T cells, other checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), contribute to immune suppression through distinct pathways.

CTLA-4 limits T-cell priming by outcompeting CD28 for binding to B7 molecules on antigen-presenting cells, reducing the likelihood of a robust immune response before PD-L1-mediated suppression occurs. LAG-3 binds to major histocompatibility complex class II (MHC-II), limiting T-cell proliferation, while TIM-3 interacts with galectin-9, promoting T-cell exhaustion. The co-expression of these checkpoints alongside PD-L1 is a hallmark of immune-resistant lung tumors, complicating treatment strategies that rely solely on PD-L1 blockade.

Laboratory Assessments Of PD-L1

PD-L1 evaluation guides immunotherapy decisions, with laboratory assessments providing quantitative and qualitative measures of its presence on tumor cells and immune infiltrates. Immunohistochemistry (IHC) remains the primary detection method, using monoclonal antibodies to stain tissue samples and determine the percentage of positive cells. Scoring systems such as the Tumor Proportion Score (TPS) for NSCLC and the Combined Positive Score (CPS) help stratify patients for immune checkpoint inhibitors. The accuracy of IHC results depends on antibody selection, tissue preparation, and interobserver variability, necessitating stringent quality control.

Beyond IHC, alternative techniques refine PD-L1 assessment. RNA-based methods, such as reverse transcription-polymerase chain reaction (RT-PCR), provide quantitative analysis by measuring PD-L1 mRNA levels. Next-generation sequencing (NGS) offers insights into the genomic and transcriptomic landscape influencing PD-L1 regulation, identifying co-existing mutations and expression signatures linked to immunotherapy response. Liquid biopsy approaches, including circulating tumor cells (CTCs) and extracellular vesicles carrying PD-L1, are emerging as non-invasive methods to monitor expression changes over time, helping track tumor evolution and treatment resistance.