4.8 Article

Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer

Journal

SCIENCE ADVANCES
Volume 8, Issue 5, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abl5420

Keywords

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Funding

  1. European Research Council (ERC) under the European Union [677542]
  2. Barts Charity [MGU0343, MRCU0032]
  3. Wellcome Trust
  4. Royal Society [107613/Z/15/Z]
  5. Bayer AG

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Inflammation is linked to colorectal cancer, and aspirin mediates its immunomodulatory effects by increasing the concentration of aspirin-triggered specialized proresolving mediators (AT-SPM) and reducing the expression of programmed cell death protein-1. These findings reveal a central role for AT-SPM in regulating inflammation-associated colorectal cancer.
Inflammation is linked with carcinogenesis in many types of cancer including colorectal cancer (CRC). Aspirin is recommended for the prevention of CRC, although the mechanism(s) mediating its immunomodulatory actions remain incompletely understood. Here, we demonstrate that aspirin increased concentrations of the immune-regulatory aspirin-triggered specialized proresolving mediators (AT-SPM5), including AT-lipoxin A(4) and AT-resolvin D1, in colonic tissues during inflammation-associated CRC (I-CRC). Aspirin also down-regulated the expression of the checkpoint protein programmed cell death protein-1 in macrophages and CD8(+) T cells from the colonic mucosa. Inhibition of AT-SPM biosynthesis or knockout of the AT-SPM receptor Alx/Fpr2 reversed the immunomodulatory actions of aspirin on macrophages and CD8(+) T cells and abrogated its protective effects during I-CRC. Furthermore, treatment of mice with AT-SPM recapitulated the immune-directed actions of aspirin during I-CRC. Together, these findings elucidate a central role for AT-SPM in mediating the immune-directed actions of aspirin in regulating I-CRC progression.

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