Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Mechanisms of immune checkpoint blockade in modulating tumor evolution remain unclear.
• Understanding therapy-induced genomic and immune changes is crucial for advanced melanoma treatment.

Purpose of the Study:

• To investigate genomic alterations and immune microenvironment changes in melanoma patients during nivolumab therapy.
• To elucidate the mechanism of action of nivolumab in modulating tumor evolution.

Main Methods:

• Whole-exome, transcriptome, and T-cell receptor sequencing of tumors from 68 advanced melanoma patients.
• Analysis of genomic and immune profiles before and after nivolumab initiation.

Main Results:

• Responding patients showed reduced mutation and neoantigen load, with evidence of clonal evolution and selection against neoantigenic mutations.
• Nivolumab therapy increased distinct immune cell subsets and activated immune checkpoint genes, correlating with response.
• Temporal T-cell receptor sequencing revealed expansion of T-cell clones alongside neoantigen loss.

Conclusions:

• Nivolumab modulates tumor evolution through genomic selection and immune microenvironment remodeling.
• Genomic profiling provides insights into nivolumab's mechanism of action in melanoma.