Discovery of Small Molecules for the Reversal of T Cell Exhaustion

Marro, Brett S.; Zak, Jaroslav; Zavareh, Reza Beheshti; Teijaro, John R.; Lairson, Luke L.; Oldstone, Michael B. A.

doi:10.1016/j.celrep.2019.10.119

Cited by 39 publications

(30 citation statements)

References 66 publications

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“…The link to CD8 + T-cell exhaustion was not just seen in MIS-C but in KD as well, a disease whose etiology remains elusive. Just as therapeutic approaches reversing exhaustion are actively being explored to treat cancer( Marro et al, 2019 ), approaches that induce exhaustion may be effective for diseases such as MIS-C where its absence is pathological. TBX21 and the other key drivers of the skyblue module are promising therapeutic targets in this regard.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children

Beckmann¹,

Comella²,

Cheng³

et al. 2020

Preprint

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Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8+ T-cells and CD56dimCD57+ NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21, a central coordinator of exhausted CD8+ T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children

Beckmann¹,

Comella²,

Cheng³

et al. 2020

Preprint

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“…In addition, small molecules are being developed to counter T-cell exhaustion and enhance T-cell cytotoxicity by acting on intracellular signaling cascades (Fig. 3) [329-331]. The rationale behind combined T-cell modulation is multifaceted and has ample support by preclinical evidence: to increase response rates, deplete Treg, overcome the epigenetic stability of Tex, and facilitate long-term benefit due to development of T-cell memory [283, 332-343].…”

Section: Therapeutic Immunomodulationmentioning

confidence: 99%

Immune Modulation in Lung Cancer: Current Concepts and Future Strategies

Gaissmaier

Christopoulos

2020

Respiration

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Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15–25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future.

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“…Based on our findings, we would hypothesize that targeting the Ca 2+ pathway or mechanistically linked molecules to re-establish a correct signalling balance could have a positive impact on effector functions. In this respect, a recent screen identified ingenol mebutate, an activator of PKCs, for its ability to revert T cell exhaustion ( Marro et al, 2019 ). Mechanistically, this compound was able to complement ionomycin signal for efficient reinvigoration of virus-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

Marotel

Villard

Drouillard

et al. 2021

eLife

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Antiviral effectors such as Natural Killer (NK) cells have impaired functions in chronic hepatitis B (CHB) patients. The molecular mechanism responsible for this dysfunction remains poorly characterized. We show that decreased cytokine production capacity of peripheral NK cells from CHB patients was associated with reduced expression of NKp30 and CD16, and defective mTOR pathway activity. Transcriptome analysis of patients NK cells revealed an enrichment for transcripts expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion employ common mechanisms. In particular, the transcription factor TOX and several of its targets were over-expressed in NK cells of CHB patients. This signature was predicted to be dependent on the calcium-associated transcription factor NFAT. Stimulation of the calcium-dependent pathway recapitulated features of NK cells from CHB patients. Thus, deregulated calcium signalling could be a central event in both T cell exhaustion and NK cell dysfunction occurring during chronic infections.

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Discovery of Small Molecules for the Reversal of T Cell Exhaustion

Cited by 39 publications

References 66 publications

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children

Immune Modulation in Lung Cancer: Current Concepts and Future Strategies

Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

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