WCLC 2025 - Posters & ePosters-P3.03.14 PCSK9-Mediated Immune Escape as a Mechanism of Acquired Resistance to PD-1/PD-L1 Blockade

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This study investigates the role of PCSK9 in acquired immune resistance (AIR) to PD-1 blockade therapy in non-small cell lung cancer (NSCLC). Despite the clinical successes of immune checkpoint blockade (ICB), many patients eventually develop resistance, limiting long-term efficacy. The researchers used patient data and mouse models to explore mechanisms underlying AIR. Single-cell RNA sequencing and in vitro assays revealed that PCSK9 is significantly upregulated in NSCLC tumors that develop resistance to PD-1 inhibitors. Mechanistically, PCSK9 overexpression impairs CD8+ T cell function and antitumor immunity by activating the KEAP1-NRF2-SLC7A11 pathway. Specifically, PCSK9 promotes lysosomal degradation of KEAP1, which leads to activation of NRF2 signaling and subsequent immune evasion. Loss of KEAP1 similarly reduces CD8 T cell activity and contributes to resistance. Importantly, the study demonstrates that combined inhibition of PCSK9 and PD-1 can restore antitumor immunity and overcome acquired resistance in vivo. These findings suggest that PCSK9 is a critical mediator of immune escape in NSCLC during PD-1 blockade therapy, highlighting the potential of combining PCSK9 inhibitors with anti-PD-1 antibodies. Supporting this translational approach, a phase II clinical trial (ChiCTR2500099426) is underway to test the efficacy of tolecimab, an anti-PCSK9 antibody, combined with PD-1 blockade in NSCLC patients who have failed first-line immunotherapy. Overall, this work identifies PCSK9 upregulation and KEAP1 degradation as key drivers of acquired resistance to PD-1 therapy and proposes a novel combination strategy to improve outcomes for patients with resistant NSCLC.

Asset Subtitle

Guang-Ling Jie

Meta Tag

Speaker Guang-Ling Jie

Topic Tumor Biology – Translational Biology

Keywords

PCSK9

acquired immune resistance

PD-1 blockade therapy

non-small cell lung cancer

immune checkpoint blockade

CD8+ T cell dysfunction

KEAP1-NRF2-SLC7A11 pathway

lysosomal degradation of KEAP1

immune evasion

combination therapy with PCSK9 inhibitors and anti-PD-1 antibodies