Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies

Gurusamy, Devikala; Henning, Amanda N.; Yamamoto, Tori N.; Yu, Zhiya; Zacharakis, Nikolaos; Krishna, Sri; Kishton, Rigel J.; Vodnala, Suman K.; Eidizadeh, Arash; Li, Jia; Kariya, Christine M.; Black, Mary A.; Eil, Robert L.; Palmer, Douglas C.; Pan, Jenny H.; Sukumar, Madhusudhanan; Patel, Shashank J.; Restifo, Nicholas P.

doi:10.1016/j.ccell.2020.05.004

Cited by 118 publications

(111 citation statements)

References 52 publications

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“…229 Loss-of-function studies in T cells have identified genes that, when deleted, can enhance T-cell responses, [230][231][232][233][234] such as p38 MAPK (MAPK14). 235 Many groups are also investigating whether candidate transcription factors, such as c-Jun, 236 or synthetic cell receptors, 237,238 such as the IL-2 receptor, 239 can be overexpressed to reprogramme T cells, prevent exhaustion, or convert suppressive extracellular signals into activating signals. A first-in-human Phase 1 clinical trial of multiplex CRISPR-Cas9 gene editing in T cells from three patients with advanced, refractory cancer (two patients with myeloma and one with sarcoma) demonstrated that this approach is safe and feasible.…”

Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

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Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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“…Another clue as to how blocking signaling cascades may overlap to improve T cell therapies was recently identified by the Restifo group ( 155 ). They used a multi-phenotype CRISPR screen to identify more than 25 targets downstream of T cell activation.…”

Section: Modulating Metabolism To Enhance Adoptive T Cell Therapymentioning

confidence: 99%

“…They used a multi-phenotype CRISPR screen to identify more than 25 targets downstream of T cell activation. They identified the stress response p38 MAP kinase as a key driver involved in preventing T cell mediated tumor immunity ( 155 ). This finding reinforces previous studies that elegantly demonstrated that ER stress, a target regulated by p38, impairs intratumoral T cell protein translation of cytotoxic molecules and regulates mitochondrial and T cell exhaustion ( 156 – 159 ).…”

Section: Modulating Metabolism To Enhance Adoptive T Cell Therapymentioning

confidence: 99%

Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

et al. 2021

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Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.

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“…Both pathways will inhibit cyclin dependent kinase 4 (CDK4) and CDK6 to maintain the retinoblastoma (RB) protein hypo-phosphorylated, preventing cell cycle transition from G1 to S phase, leading to senescence [36][37][38][39][40]. In addition, telomere-independent, DNA damage-associated cellular senescence has also been linked to p38 mitogen-activated protein kinase (p38MAPK) signaling in activated T cells [41,42].…”

Section: Senescencementioning

confidence: 99%

“…Furthermore, senescent T lymphocytes become able to suppress proliferation of normal T cells and promote tumor immune evasion [164]. In anti-CD3 + IL-2 stimulated T cells, inhibition of p38MAPK signaling proved to be helpful to reverse the senescence phenotype of CD8+ T cells by increasing their proliferation and functionality [41,42].…”

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 99%

Advances in Cellular Immunotherapy: Understanding and Preventing T-cell Dysfunction

Janelle¹,

Delisle²

2020

Preprint

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Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.

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Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies

Cited by 118 publications

References 52 publications

Promises and challenges of adoptive T-cell therapies for solid tumours

Promises and challenges of adoptive T-cell therapies for solid tumours

Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

Advances in Cellular Immunotherapy: Understanding and Preventing T-cell Dysfunction

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