Inhibition of Calcium Signaling Prevents Exhaustion and Enhances Anti‐Leukemia Efficacy of CAR‐T Cells via SOCE‐Calcineurin‐NFAT and Glycolysis Pathways

Shao, Mi; Teng, Xinyi; Guo, Xin; Zhang, Hao; Huang, Yanfang; Cui, Jiazhen; Si, Xiaohui; Ding, Lijuan; Wang, Xiu-Jian; Li, Xia; Shi, Jimin; Zhang, Mingming; Kong, Delin; Gu, Tianning; Hu, Yongxian; Qian, Pengxu; Huang, He

doi:10.1002/advs.202103508

Cited by 27 publications

(28 citation statements)

References 66 publications

(52 reference statements)

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“…For example, the genetic absence of PD-1 increases T cell exhaustion in mice, presumably due to overactivation 70 . In agreement, several methods to dampen T cell overactivation have been shown to reduce T cell exhaustion, including transient pharmacological resting or inhibition of calcium signaling in CAR T cells, or Cd8a KO in OTI cells [71][72][73] . Similarly, small changes in the CAR CD3ζ or CD28 signaling domains reducing activation are known to promote memory differentiation and tumor rejection 74,75 .…”

Section: Discussionmentioning

confidence: 71%

Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

et al. 2023

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Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.

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Section: Discussionmentioning

confidence: 71%

Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

et al. 2023

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“… 329 , 330 Intriguingly, most strategies to optimize CAR-T-cell products are focused on preventing the overactivation and subsequent exhaustion and/or apoptosis of CAR-T cells. 331 The approaches include modification of the manufacturing environment, 332 pre-enrichment of memory T-cell subsets, 333 CAR construct engineering to reduce signaling domains, 334 and combination of small molecules to inhibit activation signals. 335 Most of these methods have shown responses superior to those of traditional CAR-T therapy in preclinical models, which needs to be further validated for their safety and efficacy in clinical studies.…”

Section: Cellular Immunotherapymentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

169

114

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Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

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“…In vitro models are relatively less labor-intensive and easier to scale up, making them particularly favorable for studies of CAR T cell activation-related signaling pathways, which require a large number of cells harvested for biochemical assays [ 59 , 60 ]. These systems also provide a rapid method, serving as proof-of-concept assays to evaluate combinational treatment of CAR T cells with small-molecule drugs, such as the inhibitors of tyrosine kinases (i.e., Akt and Src) [ 61 , 62 ], EZH [ 63 ], ITAM [ 60 ], calcium signaling [ 64 ], and ubiquitination [ 65 ]. Further, as TAA-expressing cells grow rapidly, they can be clonally sorted and expanded to evaluate CAR T cell activation potential against different TAA densities that represent clinical settings [ 50 , 66 ].…”

Section: In Vitro Models For Car T Cell Functional Evaluationmentioning

confidence: 99%

Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models

Xiao

Brown

et al. 2022

IJMS

Self Cite

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Immunotherapy using chimeric antigen receptor (CAR) T cells is a rapidly emerging modality that engineers T cells to redirect tumor-specific cytotoxicity. CAR T cells have been well characterized for their efficacy against B cell malignancies, and rigorously studied in other types of tumors. Preclinical evaluation of CAR T cell function, including direct tumor killing, cytokine production, and memory responses, is crucial to the development and optimization of CAR T cell therapies. Such comprehensive examinations are usually performed in different types of models. Model establishment should focus on key challenges in the clinical setting and the capability to generate reliable data to indicate CAR T cell therapeutic potency in the clinic. Further, modeling the interaction between CAR T cells and tumor microenvironment provides additional insight for the future endeavors to enhance efficacy, especially against solid tumors. This review will summarize both in vitro and in vivo models for CAR T cell functional evaluation, including how they have evolved with the needs of CAR T cell research, the information they can provide for preclinical assessment of CAR T cell products, and recent technology advances to test CAR T cells in more clinically relevant models.

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Inhibition of Calcium Signaling Prevents Exhaustion and Enhances Anti‐Leukemia Efficacy of CAR‐T Cells via SOCE‐Calcineurin‐NFAT and Glycolysis Pathways

Cited by 27 publications

References 66 publications

Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models

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