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

• Published in: Science advances Vol. 8; no. 5; p. eabl5420
• Main Authors: De Matteis, Roberta, Flak, Magdalena B, Gonzalez-Nunez, Maria, Austin-Williams, Shani, Palmas, Francesco, Colas, Romain A, Dalli, Jesmond
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 04-02-2022
• Subjects: Animals; Aspirin - pharmacology; Aspirin - therapeutic use; Biomedicine and Life Sciences; CD8-Positive T-Lymphocytes - metabolism; Colitis-Associated Neoplasms; Diseases and Disorders; Immunology; Inflammation - metabolism; Macrophages - metabolism; Mice; Receptors, Formyl Peptide - metabolism; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abl5420

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-SPMs), including AT-lipoxin A
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
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.