Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies.
Ariella GlasnerSamuel A RoseRoshan SharmaHerman GudjonsonTinyi ChuJesse A GreenSham RampersaudIzabella K ValdezEmma S AndrettaBahawar S DhillonMichail SchizasStanislav DikiyAlejandra MendozaWei HuZhong-Min WangOjasvi ChaudharyTianhao XuLinas MazutisGabrielle RizzutoÁlvaro Quintanal-VillalongaParvathy ManojElisa de StanchinaCharles M RudinDana Pe'erAlexander Y RudenskyPublished in: Nature immunology (2023)
While regulatory T (T reg ) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct T reg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral T reg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual T reg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared T reg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon T reg cell deprivation in either setting, as well as in T reg cell-poor versus T reg cell-rich human lung adenocarcinomas. Accordingly, punctual T reg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.
Keyphrases
- single cell
- gene expression
- regulatory t cells
- cell therapy
- induced apoptosis
- rna seq
- dendritic cells
- oxidative stress
- transcription factor
- type diabetes
- public health
- cell proliferation
- endothelial cells
- vascular endothelial growth factor
- white matter
- drug delivery
- squamous cell carcinoma
- signaling pathway
- cell death
- metabolic syndrome
- dna methylation
- poor prognosis
- stress induced
- high throughput
- long non coding rna
- resting state
- young adults
- case report