Alzheimer’s Disease Associated Amyloid Precursor Protein and Beta-Amyloid Peptide-40 Improve Anti-Tumor Immunity in Aging T-cells
Description
Mechanisms by which aging Alzheimer’s disease (AD) patients exhibit decreased cancer incidence are mainly unknown. Here, we demonstrate that mitochondrial localization of AD-associated amyloid precursor protein (APP) and its cleaved amyloid-β 40 (Aβ40), but not the mutant APP that lacks mitochondrial localization signal, inhibits lipid stress-mediated hyperactive mitophagy in aging T-cells, improving their anti-tumor functions. B16-derived melanoma or carcinogen-induced oral cancer growth is highly reduced in 3xTg AD mice, which is attenuated by T-cell depletion. Adoptive cell transfer (ACT)-based immunotherapy using aging T-cells isolated from 3xTg-AD/Pmel mice controlled B16-melanoma tumor growth in recipient mice compared to controls. The metabolic signature of aging stress-dependent mitophagy in mouse and human T-cells showed depletion of fumarate, and exogenous fumarate supplementation or whole mitochondria transfer phenocopied aging AD T-cells with improved anti-tumor functions in aging WT T-cells. Thus, this study explains how AD is linked to improved anti-tumor immunity which limits aging-stress-dependent tumor growth.