An engineered IL-2 partial agonist promotes CD8+ T cell stemness

Mo, Fei; Yu, Zhiya; Li, Peng; Oh, Jangsuk; Spolski, Rosanne; Zhao, Liang; Glassman, Caleb R.; Yamamoto, Tori N.; Chen, Yun; Gołębiowski, Filip; Hermans, Dalton; Majri-Morrison, Sonia; Picton, Lora K.; Liao, Wei; Ren, Min; Zhuang, Xiaoxuan; Mitra, Suman; Lin, Juntang; Gattinoni, Luca; Powell, Jonathan D.; Restifo, Nicholas P.; García, K. Christopher; Leonard, Warren J.

doi:10.1038/s41586-021-03861-0

Cited by 114 publications

(84 citation statements)

References 57 publications

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“…Based on preclinical observations ( 7 , 30 , 165 ), a transient preincubation in a more physiologic medium inducing glucose restriction or treatment with rapamycin (or analogs) is a promising strategy to prime T cells for Tm cell differentiation ( 161 , 164 , 166 , 167 ). Along the same line, the treatment of CD8 + T cells with the engineered IL-2 partial agonist H9T improves mitochondrial fitness and promotes a stem cell–like state ( 168 ). Boosting mitochondrial elongation or cardiolipin content and blocking the repressor of OXPHOS efficiency MCJ1 are all metabolic preconditioning strategies to increase long-term survival and function of Tm cells in mouse models ( 29 , 70 , 71 ).…”

Section: Overcoming Metabolic Competition In the Tumor Microenvironment To Improve Tm Cellsmentioning

confidence: 99%

Targeting memory T cell metabolism to improve immunity

Corrado¹,

Pearce²

2022

Journal of Clinical Investigation

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Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.

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Section: Overcoming Metabolic Competition In the Tumor Microenvironment To Improve Tm Cellsmentioning

confidence: 99%

Targeting memory T cell metabolism to improve immunity

Corrado¹,

Pearce²

2022

Journal of Clinical Investigation

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“…Incubation with H9T caused sustained expression of TCF-1 and induced mitochondrial fitness, favoring sustained stem-like state of CD8 + T cells. CD8 + T cells exposed to H9T represent strong anti-tumor activity, as reported in a mouse model of melanoma ( 70 ).…”

Section: Stem-like Immune Nichesmentioning

confidence: 61%

“…Therefore, promoting the development of tumor suppressive T cells in a state not high in the differentiation is important therapeutically. Maintaining stem-like state in T cells is preferentially effective before their adoptive transferring ( 70 ). Krishna and colleagues performed a study evaluating CD8 + T cell states as a response to the question why some patients respond effectively to adoptive cell therapy (ACT), while others do not.…”

Section: Stem-like Immune Nichesmentioning

confidence: 99%

(Im)maturity in Tumor Ecosystem

Mortezaee

Majidpoor

2022

Front. Oncol.

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Tumors have special features that make them distinct from their normal counterparts. Immature cells in a tumor mass and their critical contributions to the tumorigenesis will open new windows toward cancer therapy. Incomplete cellular development brings versatile and unique functionality in the cellular tumor ecosystem, such as what is seen for highly potential embryonic cells. There is evidence that maturation of certain types of cells in this ecosystem can recover the sensitivity of the tumor. Therefore, understanding more about the mechanisms that contributed to this immaturity will render new therapeutic approaches in cancer therapy. Targeting such mechanisms can be exploited as a supplementary to the current immunotherapeutic treatment schedules, such as immune checkpoint inhibitor (ICI) therapy. The key focus of this review is to discuss the impact of (im)maturity in cellular tumor ecosystems on cancer progression, focusing mainly on immaturity in the immune cell compartment of the tumor, as well as on the stemness of tumor cells.

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“…The current view is that tumour stem cells are related to the inhibitory immune microenvironment ( Alves et al, 2021 ). At present, it is found that the stemness indices is also related to IL6/JAK/STAT3, IL-2/STAT5, and TGF-β signalling pathways ( Zhang et al, 2019 ; Liu et al, 2021 ; Mo et al, 2021 ; Zhou et al, 2021 ). Interleukins are closely related to the proliferation and function of T cells ( Ceuppens et al, 1988 ; Popmihajlov et al, 2012 ; Raeber et al, 2018 ).…”

Section: Discussionmentioning

confidence: 95%

Prognostic Value of mRNAsi/Corrected mRNAsi Calculated by the One-Class Logistic Regression Machine-Learning Algorithm in Glioblastoma Within Multiple Datasets

Zhang

Chen

Liang

et al. 2021

Front. Mol. Biosci.

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Glioblastoma (GBM) is the most common glial tumour and has extremely poor prognosis. GBM stem-like cells drive tumorigenesis and progression. However, a systematic assessment of stemness indices and their association with immunological properties in GBM is lacking. We collected 874 GBM samples from four GBM cohorts (TCGA, CGGA, GSE4412, and GSE13041) and calculated the mRNA expression-based stemness indices (mRNAsi) and corrected mRNAsi (c_mRNAsi, mRNAsi/tumour purity) with OCLR algorithm. Then, mRNAsi/c_mRNAsi were used to quantify the stemness traits that correlated significantly with prognosis. Additionally, confounding variables were identified. We used discrimination, calibration, and model improvement capability to evaluate the established models. Finally, the CIBERSORTx algorithm and ssGSEA were implemented for functional analysis. Patients with high mRNAsi/c_mRNAsi GBM showed better prognosis among the four GBM cohorts. After identifying the confounding variables, c_mRNAsi still maintained its prognostic value. Model evaluation showed that the c_mRNAsi-based model performed well. Patients with high c_mRNAsi exhibited significant immune suppression. Moreover, c_mRNAsi correlated negatively with infiltrating levels of immune-related cells. In addition, ssGSEA revealed that immune-related pathways were generally activated in patients with high c_mRNAsi. We comprehensively evaluated GBM stemness indices based on large cohorts and established a c_mRNAsi-based classifier for prognosis prediction.

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An engineered IL-2 partial agonist promotes CD8+ T cell stemness

Cited by 114 publications

References 57 publications

Targeting memory T cell metabolism to improve immunity

Targeting memory T cell metabolism to improve immunity

(Im)maturity in Tumor Ecosystem

Prognostic Value of mRNAsi/Corrected mRNAsi Calculated by the One-Class Logistic Regression Machine-Learning Algorithm in Glioblastoma Within Multiple Datasets

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