Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells

Huang, Yanfang; Si, Xiaohui; Shao, Mi; Teng, Xinyi; Xiao, Gang; Huang, He

doi:10.1186/s13045-022-01255-x

Cited by 30 publications

(30 citation statements)

References 175 publications

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“…However, it has been reported that the chloroplast genomes provided insufficient phylogenetic information to distinguish between closely related sugarcane cultivars, due to the cultivars’ recent origin and the genome conserved sequences ( Evans et al, 2019 ). In contrast, the mitochondrial genomes (mitogenome) of plants are larger ( Sloan et al, 2012 ), more plastic ( Turnel et al, 2003 ; Rubinstein et al, 2013 ; Huang et al, 2022 ), and may contain increased phylogenetic signals ( Duminil and Besnard, 2021 ). For instance, one of the main advantages of the mitogenome as a phylogenetic marker stem from the fact that its 36 genes have different rates of substitution, with some having higher rates than others, allowing relatively recent divisions to be tracked, and those having slower rates of substitution, deemed useful for elucidating deeper relationships ( Saccone et al, 1999 ; Cho et al, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Complete sequence and comparative analysis of the mitochondrial genome of the rare and endangered Clematis acerifolia, the first clematis mitogenome to provide new insights into the phylogenetic evolutionary status of the genus

Liu

Yuan

et al. 2023

Front. Genet.

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Clematis is one of the large worldwide genera of the Ranunculaceae Juss. Family, with high ornamental and medicinal value. China is the modern distribution centre of Clematis with abundant natural populations. Due to the complexity and high morphological diversity of Clematis, the genus is difficult to classify systematically, and in particular, the phylogenetic position of the endangered Clematis acerifolia is highly controversial. The use of the mitochondrial complete genome is a powerful molecular method that is frequently used for inferring plants phylogenies. However, studies on Clematis mitogenome are rare, thus limiting our full understanding of its phylogeny and genome evolution. Here, we sequenced and annotated the C. acerifolia mt genome using Illumina short- and Nanopore long-reads, characterized the species first complete mitogenome, and performed a comparative phylogenetic analysis with its close relatives. The total length of the C. acerifolia mitogenome is 698,247 bp and the main structure is multi-branched (linear molecule 1 and circular molecule 2). We annotated 55 genes, including 35 protein-coding, 17 tRNA, and 3 rRNA genes. The C. acerifolia mitogenome has extremely unconserved structurally, with extensive sequence transfer between the chloroplast and mitochondrial organelles, sequence repeats, and RNA editing. The phylogenetic position of C. acerifolia was determined by constructing the species mitogenome with 24 angiosperms. Further, our C. acerifolia mitogenome characteristics investigation included GC contents, codon usage, repeats and synteny analysis. Overall, our results are expected to provide fundamental information for C. acerifolia mitogenome evolution and confirm the validity of mitochondrial analysis in determining the phylogenetic positioning of Clematis plants.

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Section: Introductionmentioning

confidence: 99%

Complete sequence and comparative analysis of the mitochondrial genome of the rare and endangered Clematis acerifolia, the first clematis mitogenome to provide new insights into the phylogenetic evolutionary status of the genus

Liu

Yuan

et al. 2023

Front. Genet.

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“…It is thus reasonable to postulate that perturbations to either the BM or the thymic microenvironment may affect the other and be at least partly responsible for the observed immunosenescence in patients with AML. The intense interest and scrutiny of T-cell based immunotherapies in hematological malignancies lends impetus to developing novel strategies to overcome T cell immune dysfunction in vivo ( 293 ). The clinical features of CAR-T cell exhaustion in vivo have been investigated by studying cell proliferation, cytotoxicity, and the median persistence of CAR-T cells in peripheral blood, which was found to be within a range of 20 to 617 days ( 294 ).…”

Section: Discussionmentioning

confidence: 99%

The potential role of the thymus in immunotherapies for acute myeloid leukemia

Hino

Xiao

et al. 2023

Front. Immunol.

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Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease’s progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

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“…Second and third generation CAR T cells have incorporated one or two costimulatory signals, respectively. Genetic modifications to CARs for co-expression of cytokine ( 92 – 98 ), chemokine ( 99 – 101 ), or both factors ( 102 – 104 ) have been successfully used to enhance therapeutic efficacy CAR T cells.…”

Section: Brief Overview Of Car T Cell Manufacture Process and The Ass...mentioning

confidence: 99%

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

2023

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Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies.

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Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells

Cited by 30 publications

References 175 publications

Complete sequence and comparative analysis of the mitochondrial genome of the rare and endangered Clematis acerifolia, the first clematis mitogenome to provide new insights into the phylogenetic evolutionary status of the genus

Complete sequence and comparative analysis of the mitochondrial genome of the rare and endangered Clematis acerifolia, the first clematis mitogenome to provide new insights into the phylogenetic evolutionary status of the genus

The potential role of the thymus in immunotherapies for acute myeloid leukemia

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

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