Locked and loaded: strong TCR signaling primes anti-PD-1 therapy

Correa, Kristina; Dustin, Michael L.

doi:10.1016/j.it.2021.10.014

Cited by 5 publications

(7 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Once the T cells traffic to the tumor microenvironment, they are likely to encounter tumor cells expressing inhibitory molecules like PD-L1. Within this context, in vitro studies support that while PD-1 engagement on T cells can cancel costimulation by CD28, costimulation by CD2 is less sensitive to PD-1 inhibition (31). Not surprisingly, CD8 + tumor-infiltrating lymphocytes in human cancers are characterized by a quantitatively lower expression of CD2, and CD2 mRNA levels in these cells are negatively correlated with exhaustion (22).…”

Section: Discussionmentioning

confidence: 94%

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

Romain¹,

Rezvan²,

Fathi³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

The in vivo persistence of adoptively transferred T cells is predictive of anti-tumor response.Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific CAR T cells that comprise the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on Timelapse Imaging Microscopy In Nanowell Grids (TIMING) that integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We identified that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed elevated CD58 expression on pre-treatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T-cell tumor cell interactions in identifying optimal antitumor responses.

show abstract

Section: Discussionmentioning

confidence: 94%

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

Romain¹,

Rezvan²,

Fathi³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…To investigate the effects of co-blockade (CB) of Lag3 and PD-L1 in vivo , we utilised our accelerated adaptive tolerance model 2,24 to test CB potency effects following T cell reactivation ( Figure 1A ). In this model, a single high dose of [4Y]-MBP induces transient TCR signalling in vivo and upregulation of multiple immune checkponts 2 .…”

Section: Resultsmentioning

confidence: 99%

The Lag3 and PD-1 pathways govern TCR signal duration and migration of CD4⁺T cells

Sheriff,

Copland,

Lecky

et al. 2024

Preprint

View full text Add to dashboard Cite

SummaryStrong tolerogenic signalling recalibrates CD4+T cell activation in part via the PD-1 pathway. However, the contribution of other checkpoints is unknown. Here, we reveal that Lag3 and PD-L1 pathways are the major regulators of TCR signalling in adaptively tolerised CD4+T cells. Lag3 and PD-L1 co-blockade (CB) drove additive and synergistic changes in T cell activation, resulting in a transcriptional profile dominated by a NFAT-biased/ T follicular helper cell signature. Mechanistically, CB led to an enhanced duration of TCR signalling, which drove a transcriptional motif of TCR signal duration-sensitive genes. In addition, CB synergistically upregulated CCR6, leading to enhanced CCL20-dependent migration. Analysis of datasets from humans on anti-PD-1 and anti-Lag3 immunotherapy revealed upregulation of CCR6 and ICOS in blood effector memory CD4+T cells, underscoring the translational relevance of our findings. The PD-L1 and Lag3 pathways, therefore, are major regulators of TCR signal duration in adaptively tolerised CD4+T cells in vivo.

show abstract

“…Once the T cells traffic to the tumor microenvironment, they are likely to encounter tumor cells expressing inhibitory molecules like PD-L1. Within this context, in vitro studies support that while PD-1 engagement on T cells can cancel costimulation by CD28, costimulation by CD2 is less sensitive to PD-1 inhibiton (28). Not surprisingly, CD8 + tumor-infiltrating lymphocytes in human cancers are characterized by a quantitatively lower expression of CD2, and CD2 mRNA levels in these cells are negatively correlated with exhaustion (19).…”

Section: Discussionmentioning

confidence: 99%

Multidimensional single-cell analysis identifies a role of CD2-CD58 interactions for clinical antitumor T cell responses

Romain

Rezvan

Fathi³

et al. 2022

Preprint

View full text Add to dashboard Cite

The in vivo persistence of adoptively transferred T cells is predictive of anti-tumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific CAR T cells that comprise the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on Timelapse Imaging Microscopy In Nanowell Grids (TIMING) that integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with polyfunctionality. We identified that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed elevated CD58 expression on pre-treatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T-cell tumor cell interactions in identifying optimal antitumor responses.

show abstract

Locked and loaded: strong TCR signaling primes anti-PD-1 therapy

Cited by 5 publications

References 13 publications

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

The Lag3 and PD-1 pathways govern TCR signal duration and migration of CD4⁺T cells

Multidimensional single-cell analysis identifies a role of CD2-CD58 interactions for clinical antitumor T cell responses

Contact Info

Product

Resources

About

Locked and loaded: strong TCR signaling primes anti-PD-1 therapy

Cited by 5 publications

References 13 publications

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

The Lag3 and PD-1 pathways govern TCR signal duration and migration of CD4+T cells

Multidimensional single-cell analysis identifies a role of CD2-CD58 interactions for clinical antitumor T cell responses

Contact Info

Product

Resources

About

The Lag3 and PD-1 pathways govern TCR signal duration and migration of CD4⁺T cells