IL-8 blockade enhances anti-PD-1 therapeutic activity in renal cell carcinoma in a next-generation patient-derived...

Area of Science:

• Oncology
• Immunology
• Translational Medicine

Background:

• Immune checkpoint inhibitors (ICIs) are a standard treatment for advanced renal cell carcinoma (aRCC).
• Predictive biomarkers for ICI response in aRCC are lacking, and treatment resistance is a significant clinical challenge.
• Identifying factors contributing to ICI resistance is crucial for improving patient outcomes.

Purpose of the Study:

• To identify predictive biomarkers and resistance factors for anti-PD-1 therapy in patients with aRCC.
• To establish and validate a novel patient-derived xenograft (PDX) model for studying tumor-immune interactions in aRCC.
• To explore potential therapeutic strategies for overcoming PD-1 resistance in aRCC.

Main Methods:

• Comprehensive analysis of clinical samples from 51 aRCC patients treated with anti-PD-1 therapy.
• Immunohistochemical analysis of tumor microenvironment features and peripheral blood flow cytometry.
• Development of a next-generation patient-derived xenograft (NG-PDX) model using co-engraftment of tumor and immune cells in immunodeficient mice.

Main Results:

• No significant correlation was found between baseline tumor microenvironment features and anti-PD-1 response.
• Persistently elevated monocytic myeloid-derived suppressor cells (M-MDSCs) in peripheral blood were associated with non-response to anti-PD-1 therapy.
• The NG-PDX model successfully recapitulated patient-specific tumor-immune interactions, and combined PD-1 and IL-8 blockade showed potential in suppressing tumor growth.

Conclusions:

• M-MDSCs in peripheral blood may serve as a predictive biomarker for anti-PD-1 therapy in aRCC.
• NG-PDX models offer a valuable platform for evaluating novel immunotherapeutic combinations and understanding resistance mechanisms.
• Targeting IL-8 in combination with PD-1 blockade warrants further investigation for overcoming ICI resistance in aRCC.