Background and implications
Innate and adaptive immune responses to pathogens are known to vary by age at initial exposure. A classical example is the different responses observed to first exposure to Epstein–Barr virus (EBV) in early life (mild immune response; asymptomatic) versus adolescence (vigorous response often leading to infectious mononucleosis). It has long been hypothesized that differential immune responses established in early life influence risk of various cancers, including lymphomas (e.g., Hodgkin’s lymphoma, HL) and some solid tumors (e.g., nasopharyngeal carcinoma, NPC). In fact, evidence suggests that individuals initially exposed to the ubiquitous EBV during adolescence (as indicated by a diagnosis of mononucleosis) have a high risk of subsequent HL presumably due to lymphocyte hyperproliferation/expansion in response to late EBV exposure. In contrast, individuals initially exposed to EBV during adolescence appear to have a reduced risk of NPC, another EBV-associated cancer, and this is believed to be due to the development of more robust mechanisms for immune control of latent EBV infection (i.e., ability to limit chronic viral reactivation from latency) when infection first occurs late in life.
Within an early-life cohort, it would be possible to incorporate (1) a collection of biospecimens to permit assessment of exposure to specific pathogens, innate/adaptive immune responses to these pathogens, and more generalized markers of immune response, (2) a more actively followed subcohort within the larger early-life cohort in which timing of initial infections with specific pathogens and the immune responses to these pathogens can be evaluated in more detail, and (3) the use of the results from the study of this subcohort to inform findings observed in the larger early-life cohort. Childhood and young adult cancers could serve as the primary outcome in the larger cohort because they usually occur within a reasonable number of years after cohort enrollment. Adult-onset cancers would take too long to evaluate directly within the early-life cohort because they would not occur for many decades after cohort enrollment. For these cancers, the evaluation of well-established immunological markers (called intermediates) of cancer risk (e.g., IgA-rich anti-EBV antibody responses or chronic EBV reactivation/shedding) would serve as the primary outcome in the larger cohort.
Note: The above examples focus on EBV and its associated cancers because this is my personal area of expertise, but the approach is broadly applicable to other cancers known or hypothesized to be associated with infections and/or chronic immune stimulation.
Submitter
Allan Hildesheim.
Affiliation and email
National Cancer Institute, Bethesda, MD, USA.
hildesha@mail.nih.gov