High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade

Area of Science:

• Immunology
• Oncology
• Biomarker Discovery

Background:

• Immune Checkpoint Blockade (ICB) offers durable responses but faces resistance.
• Lack of robust biomarkers limits optimal ICB implementation.
• Understanding tumor microenvironment (TME) composition is key to overcoming resistance.

Purpose of the Study:

• To dissect basal TME composition predicting response to Nivolumab and prognosis.
• To identify molecular variables associated with ICB response using BCR, TCR, and HLA profiling.
• To develop and validate a predictive algorithm for ICB response.

Main Methods:

• Gene expression and cellular level analysis of TME.
• BCR, TCR, and HLA profiling.
• Machine learning model development and validation across eight metastatic melanoma cohorts.
• Single-cell RNA-seq and multispectral immunofluorescence validation.

Main Results:

• Basal intratumoral plasma cells expressing high levels of IGKC are critical for ICB efficacy.
• IGKC and IGK variants were identified in top response-related BCR clonotypes.
• CD138+ plasma-like and plasma cells were more abundant in good responders.
• A 15-gene prediction model outperformed existing scores in predicting ICB response.

Conclusions:

• Basal intratumoral IGKC and plasma cells play a major role in good response and outcomes in ICB-treated metastatic melanoma.
• This finding extends beyond the known role of T lymphocytes in ICB response.
• The developed 15-gene model shows promise for predicting ICB efficacy.