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Title:
Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution | Nature Communications
Description:
The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates immunoediting. The immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure. The cancer immunoediting hypothesis assumes the immune system sculpts the cancer genome. Here the authors show, in a mouse model, that neutral evolution outweighs the effects of immunoselection and that immune checkpoint blockade potentiates the immunoediting, switching the system to non-neutral evolution.
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Keywords {🔍}
tumor, mutations, pubmed, cancer, cell, article, samples, google, scholar, data, tumors, number, immunoediting, line, cas, model, mice, immune, wildtype, neoantigens, cells, analysis, supplementary, central, fig, mouse, expressed, nature, checkpoint, genome, rag, blockade, crc, sequencing, evolution, immunotherapy, clonal, neutral, heterogeneity, system, figure, copy, pdpdl, showed, genomic, study, control, subclonal, pathway, human,
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}\ast {\mathrm{ccf}}/\left[ {{\mathrm{cn}}_{\mathrm{ nature portfolio n-nitroso-n-methylurethane-induced balb/ }\ast {\mathrm{cn}}_{\mathrm{ privacy policy thermo fisher scientific mammalian swi/snf-related complexes prevent dc/t-cell aggregates advertising pd-1/pd-l1 pathway induces basic research studies pd-1/pd-l1 pathway renders computational genomics tools anti-pd-1/-pd-l1 antibodies pd-1/pd-l1 blockade therapy37 resulting libraries anti-pd-l1 blocking antibodies pd-1/pd-l1 pathway showed io/picard t-cell-dependent immunoselection sculpting t-cell-dependent immunoselection process cancer research anti-pd-l1-treated sample natascha hermann-kleiter anti-pd-l1-treated samples author information authors clinical research wild-type c57bl/6n mice reprints immunogenic nature dynamic nature pd-1/pd-l1 pathway pd-1/pd-l1 axis anti-pd-l1 antibodies anti pd-l1 antibodies anti-pd-l1 treated gene-editing technologies research t-cell-dependent immunoediting anti-mouse pd-l1 t-cell-independent immunoselection genotype-immunophenotype relationships t-cell-dependent mechanism original author anti-pd-l1 therapy advanced bioinformatics tools nature 410 nature 482 nature 515 nature 500
Questions {❓}
- However, as neither longitudinal samples of wild-type or immunodeficient mice nor checkpoint blockade was applied, two major questions remain unanswered: (1) To what extent is T-cell-dependent immunoselection sculpting the cancer genome?
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headline:Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution
description:The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates immunoediting. The immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure. The cancer immunoediting hypothesis assumes the immune system sculpts the cancer genome. Here the authors show, in a mouse model, that neutral evolution outweighs the effects of immunoselection and that immune checkpoint blockade potentiates the immunoediting, switching the system to non-neutral evolution.
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