A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy

Ye, Lupeng; Park, Jonathan J.; Peng, Lei; Yang, Quanjun; Chow, Ryan D.; Dong, Matthew B.; Lam, Stanley Z.; Guo, Jianjian; Tang, Erting; Zhang, Yueqi; Wang, Guangchuan; Dai, Xiaoyun; Du, Yaying; Kim, Hyunu R; Cao, Hanbing; Errami, Youssef; Clark, Paul; Bersenev, Alexey; Montgomery, Ruth R.; Chen, Sidi

doi:10.1016/j.cmet.2022.02.009

Cited by 96 publications

(89 citation statements)

References 102 publications

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“…Further analysis with transcriptomic data reveals that the enzymes catalyzing glutamate into proline are upregulated. Recent studies have revealed that the glutamine-proline axis plays an important role in many types of cancer, 35,36 but reports regarding HCC are limited. Taken together, these results suggest that the metabolites evaluated by our method are reproducible and reliable.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics‐based classification reveals subtypes of hepatocellular carcinoma

Hou

Ding

Tian

et al. 2022

Molecular Carcinogenesis

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and the prognosis varies due to its high heterogeneity, systematic evaluation of HCC is mainly based on genomic and transcriptomic features, metabolomics-based classification has yet to be reported. Here we performed RNA-seq on 50 paired samples and metabolomics analysis on 72 paired samples of both normal and tumor

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Section: Discussionmentioning

confidence: 99%

Metabolomics‐based classification reveals subtypes of hepatocellular carcinoma

Hou

Ding

Tian

et al. 2022

Molecular Carcinogenesis

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“…The immunomodulatory effects of metabolites such as Adenosine 62 , Itaconate 63-65 , and L-Proline 66 have been reported independently or in the context of disease pathogenesis. Enrichment of these metabolites as correlative markers of anti-SARS-CoV-2 immune responses further underlines their importance in immunomodulatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory innate cytokines and metabolomic signatures shape the T cell response in active COVID-19

Binayke

Zaheer

Dandotiya

et al. 2022

Preprint

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The underlying factors contributing to the evolution of SARS-CoV-2-specific T cell response during COVID-19 infection remain unidentified. To address this, we characterized innate and adaptive immune responses with metabolomic profiling longitudinally at three different time points (0-4, 7-9, and 14-16 days post-COVID-19 positivity) from young mildly symptomatic active COVID-19 patients who got infected with ancestral virus. We observed the induction of anti-RBD and SARS-CoV-2 neutralizing antibodies together with antigen-specific T cell responses as early as 0-4 days post-infection. T cell responses were largely preserved against the delta and omicron variants as compared to the ancestral strain. We determined innate immune responses at an early (days 0-4 post-COVID-19 positivity) time point of active infection in response to TLR 3/7/8 mediated activation. Interestingly, the innate immune response exhibited by the elevated levels of IL-6, IL-1β, and IL-23 correlated with a robust SARS-CoV-2-specific Th1 response at the later time point (14-16 days post covid positivity). To further understand the association of metabolic pathways induced upon active COVID-19 infection with innate and T cell response, metabolomic profiling was performed. As compared to healthy individuals, COVID-19 patients displayed a distinct metabolic signature with an enrichment of pyroglutamate, itaconate, and azelaic acid, which correlated with the SARS-CoV-2-induced innate and T cells response. Our observations reveal mechanisms and potential interventional approaches that may assist in COVID-19 therapeutics and vaccine adjuvant strategies.

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“…Driving expression of PRODH2 in CD22 CAR T leads to enhanced cancer killing, and increased lifespan in mouse leukemia models. Interestingly, lactate production increases in the PRODH2 CAR T cells [ 45 ]. Exploration of this lactate conundrum might help advance CAR T efficacy against solid tumors.…”

Section: The Hostile Tumor Microenvironmentmentioning

confidence: 99%

“…In the gain of function screen from Ye et al mentioned earlier, PRODH2 expression enhances SRC while reducing glycolysis in CD22 CAR T cells. This links with increased mitochondrial mass as well as several alterations in metabolic pathways, most notably proline and arginine metabolism [ 45 ]. When Tumor Infiltrating Lymphocytes (TILs) are treated with checkpoint inhibitors and co-stimulated with the TNFR binding protein 4-1BB, these T cells raise the SRC, exhibit both mitogenesis and mitochondrial fusion, and provide greater anti-tumor activity than TILs treated with checkpoint inhibitors alone [ 60 ].…”

Section: Spare Respiratory Capacity—a Measure Of T Cell Fitnessmentioning

confidence: 99%

Immune Cell Metabolic Fitness for Life

Bittman

2022

Antibodies

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Adoptive cell therapy holds great promise for treating a myriad of diseases, especially cancer. Within the last decade, immunotherapy has provided a significant leap in the successful treatment of leukemia. The research conducted throughout this period to understand the interrelationships between cancer cells and infiltrating immune cells winds up having one very common feature, bioenergetics. Cancer cells and immune cells both need ATP to perform their individual functions and cancer cells have adopted means to limit immune cell activity via changes in immune cell bioenergetics that redirect immune cell behavior to encourage tumor growth. Current leading strategies for cancer treatment super-charge an individual’s own immune cells against cancer. Successful Chimeric Antigen Receptor T Cells (CAR T) target pathways that ultimately influence bioenergetics. In the last decade, scientists identified that mitochondria play a crucial role in T cell physiology. When modifying T cells to create chimeras, a unique mitochondrial fitness emerges that establishes stemness and persistence. This review highlights many of the key findings leading to this generation’s CAR T treatments and the work currently being done to advance immunotherapy, to empower not just T cells but other immune cells as well against a variety of cancers.

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A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy

Cited by 96 publications

References 102 publications

Metabolomics‐based classification reveals subtypes of hepatocellular carcinoma

Metabolomics‐based classification reveals subtypes of hepatocellular carcinoma

Proinflammatory innate cytokines and metabolomic signatures shape the T cell response in active COVID-19

Immune Cell Metabolic Fitness for Life

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