Han Gyul Lee

Background/Objectives: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM). Methods: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen’s d, and sample-level coupling as Spearman ρ. Results: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs. Conclusions: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation.

List of diagnostic codes for cancer ascertainment in the Medical Expenditure Panel Survey.

This file contains a key resources table that includes details of key experimental materials and supplies used in this study.

Metabolic changes in old WT T-cells as measured by flux metabolomics.

Different therapeutic approaches utilizing the superiority of 3xTg T-cells in resisting tumor growth and progression.

Patients with Alzheimer's disease (AD) have a decreased incidence of cancer, with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD individuals compared with those with AD. In this study, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress–mediated hyperactive mitophagy in aging T cells, improving their antitumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer–based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with the TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving antitumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T cells, enhancing their antitumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched patients with AD. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance antitumor functions.Significance:The reduced cancer risk in Alzheimer's disease patients is mediated by the amyloid-β 40 peptide, which inhibits aging-dependent mitophagy in T cells to improve antitumor immunity.See related commentary by Bieberich, p. 3579

ATAD3 shuttles CerS6 to the mitochondria of aging T-cells and mitochondrial APP blocks this effect.

T-cells from human AD patients with cancer show an increase in APP levels, a decrease in mitophagy, and an increase in cytokine production.

Demographic characteristics of human APP-high vs APP-low samples.

List of diagnostic codes for cancer ascertainment in the Medical Expenditure Panel Survey.