Abstract
<jats:p>In developed countries, the rate of childhood B-cell acute lymphoblastic leukemia (B-ALL), the most common pediatric cancer with a peak incidence at 2–5 years of age, has been rising for several decades. Epidemiological studies suggest that reduced exposure to common infections in early life increases the risk of B-ALL. However, no specific infection capable of protecting against such cancer has been identified. One of the most prevalent infectious agents in humans is Epstein-Barr virus (EBV), a B-cell tropic tumor virus that infects ~95% of the global population by adult age. Paradoxically, recent studies reveal that EBV, through its signaling protein LMP1, elicits potent cytotoxic CD4+ and CD8+ T cell responses against a wide range of tumor-associated antigens (TAAs), which can recognize and attack EBV-unrelated cancer cells via shared TAAs. In developed countries, primary EBV infection is often delayed from early childhood into adolescence or young adulthood. Taken together, we hypothesized that EBV (LMP1)-induced TAA-specific T cells may help protect against some childhood B-ALL by targeting shared TAAs. If so, lack of EBV infection in early life may contribute to the rise of childhood B-ALL seen in developed countries. In this work, EBV serology assessment in pediatric B-ALL patients revealed strong exclusion of the commonest high hyperdiploid (HHD) subtype of B-ALL in children having recent primary EBV infection. Our mouse model studies demonstrated that LMP1-induced T cell immunity can eradicate some B-ALL–like leukemias via shared TAAs during the effector phase. These findings support the notion that EBV-induced anti-tumor immunity may help protect against some childhood B-ALL.</jats:p>