Antigen Recognition and T-Cell Biology

Nishimura, Michael I.; Roszkowski, J; Moore, Tamson V.; Brasic, Natasha; McKee, Mark D.; Clay, Timothy M.

doi:10.1007/0-387-27545-2_2

Cited by 19 publications

(27 citation statements)

References 116 publications

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“…However, increasing evidence suggests that TCR-pMHC affinity may not always influence the quality of effector responses [15,16,24,17]. Moreover, high-affinity TCRs used in ACT have caused serious clinical adverse events [20,21,19,18].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the emphasis on using high-affinity TCRs, we and others have suggested that enhancing TCR-pMHC affinity may not necessarily engineer a better T-cell [15–17]. For example, a TCR transgenic mouse model showed TCRs with the same affinity possess distinctly different activation requirements [15].…”

Section: Introductionmentioning

confidence: 99%

“…For example, a TCR transgenic mouse model showed TCRs with the same affinity possess distinctly different activation requirements [15]. Additionally, sister T-cell clones or progeny of individually isolated clones displayed a range of avidities for antigen [16,17]. In the clinic, high-affinity TCR-engineered T-cells induced serious on- and off-target adverse events including inflammatory colitis [18], neurological toxicity [19], and death by cardiogenic shock [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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T cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR-pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR-pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR-pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR-pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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“…The spiral density waves also enhance the collision rates of molecular clouds, which can trigger massive star formation and star cluster formation efficiently (Scoville et al 1986;Tan 2000;Nakamura et al 2012;Wu et al 2017;Fukui et al 2014;Dobashi et al 2019b). In fact, Nishimura et al (2018) recently found evidence for a cloud-cloud collision near the M17-HII region. However, streaming motions from the spiral waves can also inhibit massive star formation, a fact that has been seen in other galaxies such as M51 (Meidt et al 2013).…”

Section: Overview Of the M17 Regionmentioning

confidence: 99%

“…In Section 4, we show that the dense gas fraction and the dynamical states of the M17-HII cloud and clumps within it are different from those of M17-IRDC. And yet, both regions were suggested to be connected and are formed by colliding clouds (M17-HII: Nishimura et al 2018 andM17-IRDC: Sugitani et al 2019). In addition, Sugitani et al (2019) used the the near-infrared polarization and CO (J = 3 − 2) data to discover that the main elongation axis of M17-IRDC is perpendicular to the global magnetic fields, which are roughly perpendicular to the Galactic plane.…”

Section: 5mentioning

confidence: 99%

Large-scale Molecular Gas Distribution in the M17 Cloud Complex: Dense Gas Conditions of Massive Star Formation?

Nguyen-Luong

Nakamura

Sugitani

et al. 2020

ApJ

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The non-uniform distribution of gas and protostars in molecular clouds is caused by combinations of various physical processes that are difficult to separate. We explore this non-uniform distribution in the M17 molecular cloud complex that hosts massive star formation activity using the 12 CO (J = 1−0) and 13 CO (J = 1 − 0) emission lines obtained with the Nobeyama 45m telescope. Differences in clump properties such as mass, size, and gravitational boundedness reflect the different evolutionary stages of the M17-HII and M17-IRDC clouds. Clumps in the M17-HII cloud are denser, more compact, and more gravitationally bound than those in M17-IRDC. While M17-HII hosts a large fraction of very dense gas (27%) that has column density larger than the threshold of ∼ 1 g cm −2 theoretically predicted for massive star formation, this very dense gas is deficient in M17-IRDC (0.46%). Our HCO + (J = 1 − 0) and HCN (J = 1 − 0) observations with the TRAO 14m telescope, trace all gas with column density higher than 3 × 10 22 cm −2 , confirm the deficiency of high density ( 10 5 cm −3 ) gas in M17-IRDC.Although M17-IRDC is massive enough to potentially form massive stars, its deficiency of very dense gas and gravitationally bound clumps can explain the current lack of massive star formation.

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Targeting Cancer with Genetically Engineered TCR T Cells

Smith

Nishimura

2019

Recent Results in Cancer Research

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Antigen Recognition and T-Cell Biology

Cited by 19 publications

References 116 publications

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Large-scale Molecular Gas Distribution in the M17 Cloud Complex: Dense Gas Conditions of Massive Star Formation?

Targeting Cancer with Genetically Engineered TCR T Cells

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