Transcriptional Mechanisms of Resistance to Anti-PD-1 Therapy

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Anti-PD-1 therapy has revolutionized melanoma treatment.
• However, patient responses are heterogeneous, with some developing resistance.
• Understanding factors driving response and resistance is crucial.

Purpose of the Study:

• To investigate factors associated with response and resistance to anti-PD-1 therapy.
• To analyze autopsy specimens from a melanoma patient with heterogeneous responses.
• To correlate genetic and gene expression profiles with treatment outcomes.

Main Methods:

• Whole exome sequencing of 26 melanoma specimens (premortem and postmortem).
• Assessment of immunologic markers and gene expression in 10 cutaneous metastases.
• Analysis of lesions showing response versus progression during anti-PD-1 therapy.

Main Results:

• Melanoma was driven by biallelic inactivation of NF1.
• Lesions exhibited concordant mutational profiles and copy number alterations, suggesting linear clonal evolution.
• Progressing lesions overexpressed genes related to extracellular matrix and neutrophil function, while immunologic markers were similar.

Conclusions:

• Differential gene expression profiles, particularly involving extracellular matrix and neutrophil function, may impact anti-PD-1 therapy outcomes.
• This contrasts with the proposed primary roles of mutational and immunologic differences in determining response/resistance.
• Lesional gene expression warrants consideration as a determinant of anti-PD-1 efficacy in melanoma.