Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• PD-1 immune checkpoint blockade offers significant clinical benefits for melanoma patients.
• Understanding factors influencing innate sensitivity or resistance to anti-PD-1 therapy is crucial for improving treatment outcomes.

Purpose of the Study:

• To analyze somatic mutanomes and transcriptomes of pretreatment melanoma biopsies.
• To identify predictive biomarkers for anti-PD-1 therapy response.
• To characterize the transcriptional signature of innate anti-PD-1 resistance (IPRES).

Main Methods:

• Analysis of pretreatment melanoma biopsies for somatic mutanomes and transcriptomes.
• Identification and validation of transcriptional signatures associated with treatment response and resistance.
• Comparison of melanoma transcriptional profiles with those induced by MAPK-targeted therapy.

Main Results:

• High mutational loads and BRCA2 gene mutations correlate with improved survival in melanoma patients treated with anti-PD-1 therapy.
• Innately resistant tumors exhibit an IPRES signature characterized by upregulated genes in mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing.
• MAPK-targeted therapy induces a similar signature, suggesting cross-resistance mechanisms.

Conclusions:

• Tumor mutational burden and BRCA2 mutations are potential biomarkers for anti-PD-1 therapy response in melanoma.
• The IPRES signature represents a targetable mechanism of innate resistance to anti-PD-1 therapy.
• Targeting IPRES-associated biological processes may enhance anti-PD-1 efficacy in melanoma and other cancers.