PD-L1 is a molecule that suppresses immune responses. By interacting with the PD-1 receptor on the surface of immune cells in various tissues, PD-L1 suppresses the activity of T cells and natural killer (NK) cells. Tumors exploit this mechanism to evade immune surveillance. It is also targeted therapeutically with antibodies that block the PD-1/PD-L1 interaction in cancer treatment.
Recent research has shown that PD-L1 is not only critical for PD-1 interaction but also regulates multiple cellular processes in cancer and immune cells, including:
- TGF-β signaling and epithelial-to-mesenchymal transition (EMT)
- Epidermal growth factor receptor (EGFR) signaling
- MAPK activation
- Apoptosis
- DNA damage
- Cell proliferation and metastasis
- Cellular metabolism
Additionally, PD-L1 regulates the type I interferon (IFN-I) response. IFN-I is central to antiviral defense, immune regulation, and cell death. However, the precise mechanisms by which PD-L1 modulates the IFN-I response and affects the cell’s antiviral capabilities have remained unclear, mainly as PD-L1 blockade is increasingly studied with oncolytic viruses (OVs) for cancer therapy.
Oncolytic viruses (OVs) are viruses with natural or engineered tropism for cancer cells, which often have impaired IFN-I signaling. Preclinical and clinical studies frequently combine OVs with PD-1/PD-L1 blockade and even design OVs to reduce PD-L1 expression in the tumor microenvironment.
Cancer researchers at the Ottawa Hospital Research Institute in Canada discovered that by suppressing the IFN-I response, PD-L1 enhances susceptibility to oncolytic virus infection. PD-L1 induces a metabolic shift characterized by increased glucose uptake and glycolysis, which leads to elevated lactate production. Lactate, in turn, suppresses the IFN-I response. As a result, cancer cells with active PD-L1 expression become more susceptible to OV infection.
PD-L1 activation requires interaction with other molecules, such as CD80 and therapeutic antibodies, including atezolizumab. Although atezolizumab is an antibody against PD-L1, its binding enhances PD-L1’s intracellular signaling activity. Experiments confirmed that OV infection enhancement and IFN suppression occur only in PD-L1–expressing cells, but not in PD-L1-deficient cells. The interaction between PD-L1 and atezolizumab produces the same metabolic shifts and IFN suppression as PD-L1 alone, thereby increasing cancer cell sensitivity to viral therapy.
This discovery sheds new light on combining oncolytic viruses with PD-1/PD-L1 blockade. Oncolytic viruses increase PD-L1 expression in tumors, which can dampen the antitumor immune response. Blocking PD-L1 may enhance OV therapy by combining direct tumor cell lysis with immune system activation. Indeed, multiple studies have shown that OVs in combination with anti-PD-1/PD-L1 therapy increase immune cell infiltration into tumors and boost their activity.
These findings are supported by in vitro, in vivo, and ex vivo data from patient tumor tissues: tumors with high PD-L1 expression were more susceptible to OV infection, suggesting that PD-L1 could be a biomarker to predict the efficacy of OV therapy. The Canadian team’s discovery provides a foundation for combinatorial cancer treatments that exploit PD-L1’s signaling functions to enhance the impact of oncolytic virotherapy.
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Reference
PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway
