Anti-PD-1 antibody-mediated activation of type 17 T-cells undermines checkpoint blockade therapy

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Tumors in the LSL-K-ras^G12D murine lung cancer model exhibit resistance to anti-PD-1 antibody treatment.
• Analysis revealed increased IL-17-producing T-cells and minimal CD8⁺ T-cell activity in tumors resistant to anti-PD-1 therapy.

Purpose of the Study:

• To investigate the mechanism of anti-PD-1 resistance in lung cancer.
• To explore the role of IL-17-producing T-cells in anti-PD-1 therapy resistance.
• To identify potential therapeutic strategies to overcome resistance.

Main Methods:

• Utilized the LSL-K-ras^G12D murine lung cancer model.
• Administered anti-PD-1 antibody treatment and IL-17 neutralization.
• Performed loss-of-function studies on T-cell populations.
• Analyzed tumor biopsy samples from non-small cell lung cancer (NSCLC) patients.

Main Results:

• Concurrent anti-PD-1 and IL-17 neutralization led to robust CD8⁺ T-cell activation and a threefold reduction in tumor burden.
• Anti-PD-1-driven activation of CD4⁺ and γδTCR⁺ T-cells contributed to IL-17-mediated desensitization of CD8⁺ cytotoxic T-cells (CTLs).
• Post-therapy Th17 cell prevalence and activity predicted treatment efficacy in mice.
• Pre-therapy intratumoral CD8⁺/RORc⁺ cell ratio correlated with response to immune checkpoint blockade (ICB) in NSCLC patients.

Conclusions:

• IL-17-producing T-cells represent a novel mechanism of resistance to anti-PD-1 therapy in lung cancer.
• Targeting IL-17 in combination with anti-PD-1 therapy may enhance treatment efficacy.
• The CD8⁺/RORc⁺ cell ratio could serve as a predictive biomarker for ICB response in NSCLC.