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© Research
Publication : Science immunology

The immune system profoundly restricts intratumor genetic heterogeneity

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Science immunology - 23 Nov 2018

Milo I, Bedora-Faure M, Garcia Z, Thibaut R, Périé L, Shakhar G, Deriano L, Bousso P

Link to Pubmed [PMID] – 30470696

Sci Immunol 2018 Nov;3(29)

Tumors develop under the selective pressure of the immune system. However, it remains critical to establish how the immune system affects the clonal heterogeneity of tumors that often display cell-to-cell variation in genetic alterations and antigenic expression. To address these questions, we introduced a multicolor barcoding strategy to study the growth of a MYC-driven B cell lymphoma harboring a large degree of intratumor genetic diversity. Using intravital imaging, we visualized that lymphoma subclones grow as patches of sessile cells in the bone marrow, creating a spatially compartmentalized architecture for tumor diversity. Using multicolor barcoding and whole-exome sequencing, we demonstrated that immune responses strongly restrict intratumor genomic diversity and favor clonal dominance, a process mediated by the selective elimination of more immunogenic cells and amplified by epitope spreading. Anti-PD-1 treatment also narrowed intratumor diversity. Our results provide direct evidence that immune pressure shapes the level of intratumor genetic heterogeneity and have important implications for the design of therapeutic strategies.