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Sci Immunol. 2018 Nov 23;3(29). pii: eaat1435. doi: 10.1126/sciimmunol.aat1435.

The immune system profoundly restricts intratumor genetic heterogeneity.

Author information

1
Dynamics of Immune Responses Unit, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France.
2
INSERM U1223, 75015 Paris, France.
3
Genome Integrity, Immunity and Cancer Unit, Department of Immunology, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
4
University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, rue du Dr Roux, 75015 Paris, France.
5
Institut Curie, PSL Research University, CNRS UMR168, 11 rue Pierre et Marie Curie, 75005 Paris, France.
6
Sorbonne Universités, UPMC University Paris 06, 4 place Jussieu, 75005 Paris, France.
7
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
8
Dynamics of Immune Responses Unit, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France. philippe.bousso@pasteur.fr.

Abstract

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.

PMID:
30470696
DOI:
10.1126/sciimmunol.aat1435
[Indexed for MEDLINE]

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