The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes

Huang, Qizhao; Wu, Xia; Wang, Zhiming; Chen, Xiangyu; Wang, Lisha; Lu, Yijun; Xiong, Dan; Li, Qiao; Tian, Yuhan; Lin, Huayu; Guo, Junyi; Wen, Sheng; Dong, Wei; Yang, Xiaofan; Yuan, Yuhong; Yue, Zhengliang; Lei, Shun; Wu, Qing; Ran, Ling; Xie, Luoyingzi; Wang, Yifei; Gao, Leiqiong; Qin, Tian; Zhou, Xinyuan; Sun, Beicheng; Xu, Lifan; Tang, Zhonghui; Ye, Lilin

doi:10.1016/j.cell.2022.09.020

Cited by 194 publications

(136 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These cells have self-renewal capacity which likely explains our observation of a strong accumulation of TCR clonotypes in this population. Our data identifying such cells in CLL LNs is in line with recent studies demonstrating their presence in tumor-draining LNs of solid cancer where they are essential for efficient response to ICI therapy (Connolly et al, 2021; Huang et al, 2022).…”

Section: Discussionsupporting

confidence: 90%

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

Cid

Wong

Botana

et al. 2022

Preprint

View full text Add to dashboard Cite

Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA-sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

show abstract

Section: Discussionsupporting

confidence: 90%

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

Cid

Wong

Botana

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Naive-like CD8+ T cells are activated after antigen recognition and differentiate into SLECs or MPECs. The phenotypic heterogeneity of effector CD8+ T cells has been widely confirmed [ 19 , 20 ]. As shown in Figure S3 , among the eight cytotoxic CD8+ T cells we defined, CTL6 and 7 are closer to SLECs (CD127 low KLRG1 + T-bet high CX3CR1 high ).…”

Section: Resultsmentioning

confidence: 99%

Heterogeneity and Differentiation Trajectories of Infiltrating CD8+ T Cells in Lung Adenocarcinoma

Song

Zhao

Wang

et al. 2022

Cancers

View full text Add to dashboard Cite

CD8+ T cells infiltrating the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) are critical for establishing antitumor immunity. Nevertheless, the global landscape of their numbers, functional status, and differentiation trajectories remains unclear. In the single-cell RNA-sequencing (scRNA-seq) dataset GSE131907 of LUAD, the CD8+T cells were selected for TSNE clustering, and the results showed that they could be divided into ten subsets. The cell differentiation trajectory showed the presence of abundant transition-state CD8+ T cells during the differentiation of naive-like CD8+ T cells into cytotoxic CD8+ T cells and exhausted CD8+ T cells. The differentially expressed marker genes among subsets were used to construct the gene signature matrix, and the proportion of each subset was identified and calculated in The Cancer Genome Atlas (TCGA) samples. Survival analysis showed that the higher the proportion of the exhausted CD8+ T lymphocyte (ETL) subset, the shorter the overall survival (OS) time of LUAD patients (p = 0.0098). A total of 61 genes were obtained by intersecting the differentially expressed genes (DEGs) of the ETL subset, and the DEGs of the TCGA samples were divided into a high and a low group according to the proportion of the ETL subset. Through protein interaction network analysis and survival analysis, four hub genes that can significantly affect the prognosis of LUAD patients were finally screened, and RT-qPCR and Western blot verified the differential expression of the above four genes. Our study further deepens the understanding of the heterogeneity and functional exhaustion of infiltrating CD8+ T cells in LUAD. The screened prognostic marker genes provide potential targets for targeted therapy and immunotherapy in LUAD patients.

show abstract

“…7 ). Our understanding of the transcriptional profiles, epigenetic modifications and metabolic pathways that regulate stemlike T cells has dramatically advanced in recent years [8][9][10] . Several transcriptional factors, such as TCF1, KLF2 and LEF1, have been reported to play essential roles in driving or main taining T cell stemness 9 .…”

mentioning

confidence: 99%

Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

Cheng

Qiu

et al. 2023

Nat Metab

View full text Add to dashboard Cite

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a ‘stem-like memory’ state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.

show abstract

The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes

Cited by 194 publications

References 80 publications

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

Heterogeneity and Differentiation Trajectories of Infiltrating CD8+ T Cells in Lung Adenocarcinoma

Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

Contact Info

Product

Resources

About