Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in
Anudari Letian1,2, Eyoel Yemanaberhan Lemma1,3, Paola Cavaliere1
1Department of Biochemistry, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.
Background:
PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy.
Methods:
Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1's proximal proteome in human lung epithelial cells.
Results:
Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells.
Conclusions:
Growth factor acute regulation of PD-L1 trafficking, by contributing to the control of plasma membrane density, might contribute to the regulation of PD-L1's immune checkpoint activity, whereas the specific effects of anti-PD-L1 on mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors. Video Abstract.
Insights
Targeting PD-L1 (programmed death-ligand 1) shows limited durable responses. New research reveals growth factor control of PD-L1 trafficking and unique PD-L1 functions in mutant EGFR cells, impacting anti-PD-L1 therapy effectiveness.
Area of Science:
- Molecular and Cellular Biology
- Cancer Immunology
- Drug Discovery and Development
Background:
- Immune checkpoint inhibitor therapy targeting PD-L1 (programmed death-ligand 1) is effective in various solid tumors, including non-small cell lung cancer (NSCLC).
- Durable responses to anti-PD-L1 therapy are observed in only about 20% of patients, with reasons for response heterogeneity, particularly in mutant EGFR tumors, remaining unclear.
- Emerging evidence suggests PD-L1 possesses functions independent of PD1 signaling, but their cell-intrinsic roles and impact by anti-PD-L1 therapy across different cancer subtypes are not well understood.
Discussion:
- Quantitative microscopy and APEX2 proximity mapping were employed to elucidate PD-L1 behavior and its proximal proteome in human lung epithelial cells.
- The study identified growth factor-mediated regulation of PD-L1 recycling, influencing plasma membrane density and potentially immune checkpoint activity.
- Novel PD-L1 biology was uncovered in mutant EGFR cells, where anti-PD-L1 therapy affects cell migration, EGFR half-life, and extracellular vesicle biogenesis, unlike in wild-type EGFR cells.
Key Insights:
- Growth factors acutely regulate PD-L1 trafficking and plasma membrane density, offering a mechanism for controlling PD-L1's immune checkpoint function.
- Anti-PD-L1 therapy uniquely impacts cell-intrinsic PD-L1 functions in mutant EGFR cells, leading to reduced migration and increased extracellular vesicle production.
- These distinct effects in mutant EGFR cells may explain the poor response rates observed in mutant EGFR-driven tumors treated with anti-PD-L1 antibodies.
Outlook:
- Understanding the cell-intrinsic functions of PD-L1 and its regulation by growth factors provides new avenues for improving anti-PD-L1 therapy efficacy.
- Targeting specific PD-L1-mediated pathways in mutant EGFR tumors could overcome resistance to current immunotherapies.
- Further research into PD-L1's non-immune roles may reveal novel therapeutic strategies beyond immune checkpoint blockade.
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