Project description:Dietary methionine restriction represses growth and improves therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the immune system is unknown. Here we analyzed the CD45+ immune cells from the small intestine of control (CTRL) diet or methionine-restricted (MR) diet fed tumor-free C57BL/6J donor mice and tumor-bearing Apc <min+/-> recipient mice transplanated with feces from these diet-fed tumor-free C57BL/6J mice by scRNA-seq. Our analysis indicate that fecal microbes from methionine-restricted tumor-free C57BL/6J mice are sufficient to represss T cell activation in the small intestine of Apc <min+/-> mice.

2023-06-14 | GSE181220 | GEO

6ThiodG induces anti-tumor immunity in SCLC

Project description:6ThiodG induces anti-tumor immunity in SCLC

| PRJNA933593 | ENA

A single-cell analysis of the NK cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin

Project description:Natural killer (NK) cells are primarily responsible for tumor surveillance, and their activation entirely depends on optimal metabolic signals. The adaptation of NK cell anti-tumor responses to nutritional stress is still poorly understood. Here, based on single-cell RNA sequencing, we discovered that dietary restriction (DR) enriches the rejuvenated subset of CD27+CD11b+ NK cells and improves their activation via Eomesodermin (Eomes), a transcription factor upregulated during DR treatment. Eomes reverses the differentiation of rejuvenated to senescent NK cells by antagonizing the T-bet-Zeb2 axis while improving chemotaxis and adhesion. Furthermore, DR increases the chromatin accessibility of Eomes to genes that regulate chemotaxis and adhesion in NK cells. To summarize, tumor control under dietary restriction requires Eomes-regulated NK cell anti-tumor immunity.

2024-01-01 | GSE249425 | GEO

Exercise-Induced Engagement of the IL-15/IL15Rα axis Promotes Anti Tumor Immunity

Project description:The advent of immune checkpoint blockade has improved patient outcomes, providing durable disease control by reversing localized tumor-mediated immune-suppression and promoting anti-tumor immunity. Despite successes in melanoma and lung cancer, these therapies have largely failed in pancreatic ductal adenocarcinoma (PDA); a ‘cold’ tumor with the highest mortality rate among all major cancers. PDA is uniquely characterized by multiple intra-pancreatic tumor- and stroma-induced mechanisms of immune-suppression, and there remains a great need to explore creative approaches to improve anti-tumor immune responses in this disease. Herein, we show routine aerobic exercise provides tumor-protective benefits in murine PDA through modulation of both systemic and intra-tumoral immunity. Reversing immune-suppressive properties of both myeloid and T cell populations, we found the anti-tumor benefits of exercise require CD8 T cell activation and expansion in the tumor. Specifically, we report the sub-population of IL15Ra+ CD8 T cells is required for exercise-induced tumor protection and anti-tumor immunity, both of which are abrogated in the context IL-15 blockade. We further show that exercise-induced increases in intra-tumoral T cells are governed by adrenergic signaling and S1P-gradient dependent lymphocyte migration. Finally, we found that combination with aerobic exercise sensitizes pancreatic tumors to anti-PD-1 therapy. Overall, our work highlights the unique mechanisms governing exercise-induced tumor protection in PDA, and uncovers the importance of the interplay between systemic and intra-tumoral immunity to develop innovative strategies to reverse immune-suppression in this devastating disease.

2022-05-11 | GSE176311 | GEO

Fucosylation of HLA-DRB1 regulates CD4+T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy: Fucose Click Chemistry

Project description:Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs)—thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the MHC-II protein HLA-DRB1 in melanoma cells, triggering CD4+T cell-mediated increases in ItICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-PD1 responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity, and importantly, suggest that L-fucose is a powerful agent for safely increasing ItICs and immunotherapy efficacy in melanoma.

2022-12-16 | PXD038303 | Pride

Fucosylation of HLA-DRB1 regulates CD4+T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy: HLA-DRB1 Interactomes

2022-12-16 | PXD038068 | Pride