Long-term marine ω-3 polyunsaturated fatty acids intake in relation to incidence of colorectal cancer subclassified by macrophage infiltrates

Abstract

<p>Evidence indicates that marine omega-3 polyunsaturated fatty acid (MOPUFA) intake exerts an immunomodulatory effect to suppress the development of colorectal cancer (CRC). We hypothesized that the association of MOPUFA intake with the incidence of CRC might differ by macrophage infiltrates in tumor tissue. We utilized the Prospective Cohort Incident Tumor Biobank within the Nurses' Health Study and Health Professionals Follow-up Study, both of which repeatedly assessed diets for decades of the follow-up of 125,172 participants, among whom 2,959 developed incident CRC. To spatially identify and count M1-polarized and M2-polarized macrophages in tumor tissue, we conducted <i>in situ</i> single-cell digital image analyses using multispectral immunofluorescence [for MRC1 (CD206), MAF, IRF5, CD86, and CD68] combined with machine learning algorithms. Using the 2,959 CRC cases, inverse probability weighting was integrated into the Cox proportional hazards models to adjust for tissue macrophage data availability in 820 cases. The multivariable-adjusted hazard ratio (with 95% confidence interval) for long-term MOPUFA intake of ≥0.25 g/day (vs. <0.15 g/day) were 0.56 (0.38-0.82; <i>P</i><sub>trend</sub> = 0.004) for the incidence of CRC with the lowest-quartile M1-like macrophage density. There was no significant association of MOPUFA intake with the incidence of CRC with the second to fourth quartile M1-like macrophage densities (<i>P</i><sub>trend</sub> > 0.20). The association of MOPUFA intake with CRC incidence differed by M1-like macrophages (<i>P</i><sub>heterogeneity</sub> = 0.01), but not by M2-like macrophages. Our findings of the link between MOPUFA intake and lower incidence of CRC containing low M1-like macrophage counts provide evidence for differential influence of MOPUFAs on colorectal tumors with varying immune microenvironmental features.</p>