Are Circulating Immune Cells a Determinant of Pancreatic Cancer Risk? A Prospective Study Using Epigenetic Cell Count Measures

Abstract

Background: Evidence is accumulating that immune cells play a prominent role in pancreatic cancer etiology but prospective investigations are missing. Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study with 502 pairs of incident pancreatic cancer cases and matched controls. Relative counts of circulating immune cells (neutrophils and lymphocyte sublineages: total CD3+, CD8+, CD4+, and FOXP3+ regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. ORs with 95% confidence intervals were estimated using logistic regressions, modeling relative counts of immune cells on a continuous scale. Results: Neither relative counts of immune cell types taken individually, nor mutually adjusted for each other were associated with pancreatic cancer risks. However, in subgroup analyses by strata of lag-time, higher relative counts of Tregs and lower relative counts of CD8+ were significantly associated with an increased pancreatic cancer risks in participants diagnosed within the first 5 years of follow-up. Conclusions: These results might reflect reverse causation, due to higher relative counts of Tregs and lower counts of CD8+ cells among individuals with more advanced stages of latent pancreatic cancer, who are closer to the point of developing clinical manifest disease. Impact: We have shown, for the first time, that increased relative counts of regulatory T cells and lower relative counts of CD8+, cytotoxic T cells may be associated with pancreatic cancer risk or relatively late-stage tumor development. See related commentary by Michaud and Kelsey, p. 2176

DNA Methylation-Derived Immune Cell Proportions and Cancer Risk, Including Lung Cancer, in Black Participants

“…Fewer studies have examined immune cell subtypes. Generally, higher proportions of Tregs relative to total leukocytes or other immune cells have been associated with higher risks of lung, colorectal, breast, and pancreatic cancers [16][17][18] . On the other hand, higher relative proportions of CD8+ cells have been inversely associated with risk of lung cancer and breast cancer 16,18 .…”

“…This analysis utilizes the innovative deconvolution algorithm to predict proportions of 12 distinct immune cell subtypes 19,39,46 . Unlike previously used methods, deconvolution allows for immune cell proportions to be estimated and measured from archived blood (peripheral blood leukocytes), allowing for a prospective study design that examines the role of systemic immune response in cancer risk 18,20 .…”

“…Recent advances in high-dimensional arrays enable measurement of DNA methylation at 450,000 to 850,000 CpG oligodeoxynucleotide sites (CpGs) throughout the genome, allowing precise estimates of immune cell proportions from frozen blood samples [15][16][17][18] . Pre-diagnostic blood collection is essential to assess DNA methylation states and immune cell proportions because the cancers themselves may alter these profiles 19 .…”

Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study

“…21 Additionally, another prospective study indicated that an increase in the relative numbers of regulatory T (Treg) cells and a decrease in the relative numbers of CD8 + cytotoxic T cells may be linked to an increased risk of pancreatic cancer or the progression to a more advanced stage of the disease. 22 However, currently, the role of circulating immune cells is often neglected in pancreatic cancer researches. The causal relationship between circulating immune cells and pancreatic cancer is unclear.…”

“…A decrease in the overall proportion of lymphocytes and an elevated CD4/CD8 ratio in pancreatic cancer have been observed in comparison with healthy individuals 21 . Additionally, another prospective study indicated that an increase in the relative numbers of regulatory T (Treg) cells and a decrease in the relative numbers of CD8 + cytotoxic T cells may be linked to an increased risk of pancreatic cancer or the progression to a more advanced stage of the disease 22 . However, currently, the role of circulating immune cells is often neglected in pancreatic cancer researches.…”