Abstract Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for ∼15% of pediatric cancer-related deaths. Despite these relatively poor outcomes in high-risk disease, children under 18 months of age often demonstrate spontaneous tumor regression. The mechanisms leading to spontaneous NBL regression are incompletely described and likely consist of both cell intrinsic and extrinsic features. In contrast to the relatively poor immunogenicity of high-risk NBL, regressing tumors have a distinct immunological “signature” suggesting the immune system may play a critical role in this process. The function of individual immune cells is dynamic in early life as the immune system develops. We posited that functional differences in the infant immune system could provide inherent advantages for antitumor immunity against NBL. In particular, neonatal CD8+ T cells have increased proliferative potential, enhanced cytokine production, and may resist exhaustion relative to their adult counterparts. We hypothesized the enhanced functionality of neonatal T cells is controlled by the utilization of distinct pathways of cellular metabolism. We identified that following in vitro activation, neonatal CD8+ T cells have distinct RNA expression profiles of genes related to cell metabolism compared to adult T cells. The expression of pathways associated with central carbon metabolism were markedly different between neonatal and adult T cells. Pyruvate serves as the central metabolite hub for these processes, and isotopomer tracing revealed that neonatal T cells process pyruvate differently than adult cells. Extracellular pyruvate supplementation was essential for the proliferation and effector cytokine production in neonatal CD8+ T cells. Neonatal T cells had a preferential conversion of pyruvate to alanine indicating an enhanced use of the glutamic pyruvate transaminase (GPT) reaction. Ongoing studies will identify the subcellular compartmentalization (i.e. cytoplasmic, mitochondrial) and impact of NBL-imposed metabolic constraints in the tumor microenvironment on this newly identified metabolic feature of neonatal T cells. Citation Format: Elinor DeCleene, Amy Reynolds, Daniela Vega-Mendoza, Rebeca Rodriguez, Mingkee Achom, Naomei Lidman, Jose Almeida-Santos, Grace Rish, Samuel Markson, Jared H. Rowe. Rewiring of pyruvate metabolism in neonatal CD8+ T cells alters functionality and antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3290.
Decleene et al. (Fri,) studied this question.