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Published on: April 30, 2021
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
Nadeem Riaz1, Jonathan J Havel2, Vladimir Makarov3
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
Insights
Immune checkpoint blockade with nivolumab alters tumor evolution by reducing mutations and selecting against neoantigens in melanoma. This therapy also reshapes the tumor immune microenvironment, enhancing T-cell responses.
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.
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