Paramita Chakraborty

Sphingosine 1-phosphate (S1P) is a potent bioactive sphingolipid that plays essential roles in regulating various immune responses, including lymphocyte trafficking, immune cell differentiation, and immunosurveillance. Different immune responses to S1P arise from the diverse Sphingosine 1-phosphate receptors (S1PRs) expressed on the cell surface, shaping unique, context-dependent responses to S1P. Beyond surface receptor engagement, intracellular S1P signaling is also being recognized as a crucial modulator of immune cell responses. Furthermore, the multifaceted S1P signaling axis has emerged as a key regulator of immune responses within the tumor microenvironment (TME), influencing both innate and adaptive immune cell behavior to facilitate tumor progression. A deeper mechanistic understanding of S1P signaling and its impact on immune cell fate is essential for developing novel therapeutic strategies to enhance anti-tumor responses. This review summarizes our current knowledge of how S1P influences immune cell function, with a specific focus on S1PR-dependent and S1PR-independent cellular signaling pathways. We also examine the alterations in immune cell responses that occur within the TME and current therapeutic strategies targeting S1P signaling.

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.