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Abstract The association between Alzheimer’s disease (AD) and lower cancer incidence has been observed in several epidemiological studies without much mechanistic insight. We aimed to understand this cancer resistance mechanism linked to AD and exploit it for broader cancer therapies. A hallmark of AD is the accumulation of amyloid precursor protein (APP) in neuronal mitochondria, inhibiting mitophagy, abrogating the clearance of dysfunctional mitochondria, and contributing to AD pathology. In addition to neurons, mitophagy plays an important role in T-cells, where excessive ceramide-dependent mitophagy in aging T-cells inhibits their energy metabolism and limits their anti-tumor functions. Thus, attenuation of ceramide-dependent mitophagy plays a favorable role in enhancing aging T-cell anti-tumor function. Given that APP is also processed in T-cells, we hypothesized that APP accumulates aberrantly in aging Alzheimer’s T-cells, inhibiting mitophagy and enhancing T-cell anti-tumor activity. Employing techniques of lipidomics, metabolomics, imaging, molecular biology, and genetic models, we show that AD T-cells from a mouse model and human patients are protected against aging-associated ceramide-dependent mitophagy, which enhanced their secretion of inflammatory anti-tumor cytokines. The excessive localization of APP to the T-cell mitochondria, where it inhibits the accumulation of ceramide synthase 6 (CerS6) and C14/C16-ceramides, attenuated the levels of mitophagy and protected the Alzheimer’s T-cells from metabolic defects observed in aging, namely protecting against the exhaustion of fumarate pools. Both in vitro and in vivo re-supplementation of fumarate to aging WT mouse T-cells effectively rescued their viability, cytokine production, and tumor killing capacity both in vitro and in adoptive T-cell transfers to mice with melanoma, functionally mimicking the AD phenotype. The fumarate supplementation also led to a decrease in ceramide-dependent mitophagy in the WT aging T-cells, indicating an interplay between ceramide-dependent mitophagy and fumarate metabolism which contributes to the protection of the anti-tumor function in aging AD T-cells. Moreover, we show that Alzheimer’s mice that express APP in the brain and T-cells, but not AD mice that express APP only in the brain, are protected against the growth of both carcinogen-induced and allografted tumors. Finally, transfer of mitochondria from AD T-cells to aging WT T-cells improved their metabolic fitness and anti-cancer functions. In summary, we show that AD-associated APP improves anti-tumor immunity of aging T-cells by inhibiting ceramide-mediated lethal mitophagy and restoring mitochondrial fumarate metabolism. These data provide a novel mechanism to explain reduced cancer incidences in AD patients. Citation Format: Mohamed Faisal Kassir, Han G. Lee, Natalia Oleinik, Wyatt Wofford, Chase Walton, F. Cansu Atilgan, Paramita Chakraborty, Kubra Calisir, Ozgur Sahin, Shikhar Mehrotra, Besim Ogretmen. Alzheimer's disease-associated amyloid precursor protein improves anti-tumor immunity by inhibiting ceramide-mediated lethal mitophagy and restoring mitochondrial fumarate metabolism in aging T-cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3969.
Kassir et al. (Fri,) studied this question.