Revisiting T Cell Tolerance as a Checkpoint Target for Cancer Immunotherapy

Nüssing, Simone; Trapani, Joseph A.; Parish, Ian A.

doi:10.3389/fimmu.2020.589641

Cited by 24 publications

(16 citation statements)

References 199 publications

(302 reference statements)

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“…Several factors impact the persistence of CAR T-cells in patients, including activation-induced cell death (AICD) and peripheral tolerance, which may be described as a state of antigen recognition but lack of reactivity toward cancer cells [ 34 ]. Tolerance occurs in situations of chronic low-grade inflammation (para-inflammation) and it is dependent on the context of different cancer subtypes.…”

Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

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Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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“…In the context of different susceptibilities to blocking PD-1/PD-L1 signaling in patients [87,91], targeting only this pathway might not be enough to restore CTL activities [92]. But future studies are needed to clarify which parameters actually induce tolerance in the tumor context [93,94]. In conclusion, inhibition of mTOR restrains effector responses in CD8 + T cells but stimulates memory formation and may promote exhaustion.…”

Section: Cd8 + T Cellsmentioning

confidence: 99%

mTOR‐dependent immunometabolism as Achilles' heel of anticancer therapy

Braun

Weichhart

2021

Eur J Immunol

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Immune cells are important constituents of the tumor microenvironment and essential in eradicating tumor cells during conventional therapies or novel immunotherapies. The mechanistic target of rapamycin (mTOR) signaling pathway senses the intra‐ and extracellular nutrient status, growth factor supply, and cell stress‐related changes to coordinate cellular metabolism and activation dictating effector and memory functions in mainly all hematopoietic immune cells. In addition, the mTOR complex 1 (mTORC1) and mTORC2 are frequently deregulated and become activated in cancer cells to drive cell transformation, survival, neovascularization, and invasion. In this review, we provide an overview of the influence of mTOR complexes on immune and cancer cell function and metabolism. We discuss how mTOR inhibitors aiming to target cancer cells will influence immunometabolic cell functions participating either in antitumor responses or favoring tumor cell progression in individual immune cells. We suggest immunometabolism as the weak spot of anticancer therapy and propose to evaluate patients according to their predominant immune cell subtype in the cancer tissue. Advances in metabolic drug development that hold promise for more effective treatments in different types of cancer will have to consider their effects on the immune system.

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“…Treg cells are the major cellular compartment tasked with the suppression of excessive (or inappropriate) T and B cell responses that may cause tissue damage if left unchecked [20][21][22][23][24]. Treg cells are highly diverse in terms of differentiation and activation stages and arise either from T cell precursors in the thymus (tTregs) or naïve CD4 + T cells initiated during antigen-priming in secondary lymphoid tissues (iTregs).…”

Section: Treg Cell-targeted Therapiesmentioning

confidence: 99%

Chemokine Receptor-Targeted Therapies: Special Case for CCR8

Moser

2022

Cancers

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Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Recent reports revealed the selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. In this review, I summarize our current knowledge about the cellular distribution and function of CCR8 in physiological and pathophysiological processes. The discussion includes an assessment of how the removal of CCR8-expressing cells might affect both anti-tumor immunity as well as immune homeostasis at remote sites. Based on these considerations, CCR8 appears to be a promising novel target to be considered in future translational research.

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Revisiting T Cell Tolerance as a Checkpoint Target for Cancer Immunotherapy

Cited by 24 publications

References 199 publications

Improving CAR T-Cell Persistence

Improving CAR T-Cell Persistence

mTOR‐dependent immunometabolism as Achilles' heel of anticancer therapy

Chemokine Receptor-Targeted Therapies: Special Case for CCR8

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