PD-1 and LAG-3 Dominate Checkpoint Receptor-Mediated T-cell Inhibition in Renal Cell Carcinoma

Area of Science:

• Immunology
• Oncology
• Cancer Therapy

Background:

• Programmed cell death protein 1 (PD-1) pathway inhibitors are approved for various cancers, including renal cell carcinoma (RCC).
• While improving overall survival, current PD-1 therapies often lack durable responses in most RCC patients.
• Combination immunotherapy strategies are being explored to enhance clinical efficacy.

Purpose of the Study:

• To identify the most effective checkpoint blockade combination for renal cell carcinoma (RCC) patients.
• To investigate the co-expression of inhibitory receptors (iRs) on tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs).
• To assess the functional impact of dual PD-1 and other iR blockade on T-cell responses.

Main Methods:

• Isolation of TILs and PBMCs from RCC patients undergoing primary tumor surgery.
• Multicolor flow cytometry to analyze the co-expression of PD-1, LAG-3, Tim-3, BTLA, and CTLA-4 on T-cell populations.
• In vitro stimulation of TILs with PD-1 ± LAG-3 or Tim-3 specific antibodies, followed by intracellular cytokine staining to assess T-cell function.

Main Results:

• Increased frequencies of PD-1+, LAG-3+, and Tim-3+ cells were observed on CD4+ and CD8+ TILs compared to PBMCs.
• The most common inhibitory receptor combination on TILs was PD-1 and LAG-3.
• Dual blockade of PD-1 and LAG-3 significantly increased IFNγ release, unlike PD-1 and Tim-3 blockade.

Conclusions:

• Dual blockade of PD-1 and LAG-3 represents a promising combination immunotherapy strategy for renal cell carcinoma.
• This combination enhances T-cell effector function, potentially overcoming resistance to single-agent PD-1 therapy.
• Further clinical investigation of PD-1 and LAG-3 blockade in RCC is warranted.