Research ArticleCANCER IMMUNOLOGY

The immune system profoundly restricts intratumor genetic heterogeneity

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Science Immunology  23 Nov 2018:
Vol. 3, Issue 29, eaat1435
DOI: 10.1126/sciimmunol.aat1435

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Immunoediting of polychromatic tumors

As tumors grow, they evolve genetically. The resulting genetic heterogeneity contributes to the emergence of variants that may ultimately display increased resistance to immune effector mechanisms and enhanced metastatic potential. Milo et al. used multicolor barcoding of a mouse lymphoma line to determine whether increased immune selection pressure by the host accelerates the emergence of dominant clones. When barcoded male lymphoma cells were given to male and female recipients, clonal dominance emerged more rapidly in female recipients because more neoantigens were available to elicit a host T cell response. Checkpoint blockade with anti–PD-1 promoted a similar contraction of intratumor diversity. These findings provide fresh insights into the immunoediting mechanisms by which active antitumor immunity directs the in vivo selection of less immunogenic tumor variants.

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.

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