HLA class II immunogenic mutation burden predicts response to immune checkpoint blockade

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Human leukocyte antigen (HLA) class I neoantigens are linked to immune checkpoint blockade (ICB) response.
• The role of HLA class II-restricted neoantigens in ICB response remains less understood.

Purpose of the Study:

• To computationally assess HLA class II immunogenic mutation (IMM) burden in patients with melanoma and lung cancer treated with ICB.
• To evaluate the impact of HLA class II IMMs on clinical outcomes and tumor microenvironment.

Main Methods:

• Analysis of whole-exome sequence data from ICB-treated melanoma and non-small-cell lung cancer (NSCLC) cohorts.
• Utilized MHCnuggets to estimate HLA class II IMM burdens and mutation clonality.
• Correlated HLA class II IMM burden with clinical outcomes, T-cell infiltration, and gene expression.

Main Results:

• Responding tumors showed significantly higher HLA class II IMM burden in both melanoma and NSCLC.
• Higher HLA class II IMM burden correlated with longer survival, especially in NSCLC with low heterogeneity.
• Distinct HLA class I and II IMM landscapes suggest complementary roles in tumor rejection.
• Increased HLA class II IMM burden associated with CD4+ T-cell infiltration and an inflamed tumor microenvironment.

Conclusions:

• HLA class II IMM burden is a significant predictor of longer survival in patients receiving ICB.
• HLA class II IMMs may influence ICB response distinctly and complementarily to HLA class I.