Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) and its ligand PD-L1 show efficacy in cancers like non-small cell lung cancer (NSCLC).
• Therapeutic resistance to anti-PD-L1 (aPD-L1) antibodies is a significant clinical challenge, and its underlying mechanisms remain incompletely understood.

Purpose of the Study:

• To investigate novel mechanisms of resistance to aPD-L1 antibody treatment in non-small cell lung cancer.
• To identify specific molecular players contributing to therapeutic failure in PD-L1 blockade therapy.

Main Methods:

• Identification and characterization of secreted PD-L1 splicing variants in aPD-L1-resistant NSCLC patients.
• Co-culture experiments using induced pluripotent stem cell (iPSC)-derived CD8 T cells and cancer cells to assess decoy function of secreted PD-L1.
• In vivo studies using a MC38 syngeneic xenograft model to evaluate resistance induction and therapeutic efficacy of anti-PD-1 (aPD-1) antibodies.

Main Results:

• Two unique secreted PD-L1 variants lacking the transmembrane domain were identified in resistant NSCLC patients.
• These secreted PD-L1 variants acted as decoys, binding aPD-L1 antibodies and preventing T cell-mediated tumor killing.
• Even a small proportion (1%) of cells expressing secreted PD-L1 variants induced resistance to aPD-L1 blockade in vivo.
• Treatment with aPD-1 antibodies successfully overcame the resistance mediated by these secreted PD-L1 variants.

Conclusions:

• Secreted PD-L1 variants represent a novel mechanism of resistance to aPD-L1 antibody therapy in NSCLC.
• Targeting these secreted PD-L1 variants or utilizing aPD-1 antibodies may offer alternative therapeutic strategies for resistant tumors.