Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells

Jainarayanan, Ashwin Kumar; Mouroug-Anand, Nithishwer; Arbe-Barnes, Edward H.; Bush, Adam J.; Bashford-Rogers, Rachael; Frampton, Adam E.; Heij, Lara; Middleton, Mark R.; Dustin, Michael L.; Abu-Shah, Enas; Sivakumar, Shivan

doi:10.1016/j.isci.2023.106324

Cited by 3 publications

(8 citation statements)

References 46 publications

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“…These tumours present a broad repertoire of neoantigens, which direct potent anti-tumour immune responses (29,30). Indeed, in this patient cohort, sequencing of the TCR Vb chain revealed that 94% of intratumoral T cell clonotypes were unique to tumours, implying the existence of a neoantigen-specific immune response (24). Overall, this highlights the importance of neoantigens as a substrate for T eff -mediated anti-tumour immunity indeed, on the basis of this principle, pembrolizumab and nivolumab (anti-PD-1) were granted FDA-approval in 2017 for the treatment of dMMR tumours, irrespective of their tissue of origin (31).…”

Section: Why Have Icis Proved Ineffective In the Context Of Pdac?mentioning

confidence: 85%

“…Thus, the immunologically 'cold' phenotype that characterises PDAC has often been attributed to the physical exclusion of T e ff cells from the tumour microenvironment (TME) (19,20). However, recent studies have challenged this paradigm, identifying heterogenous baseline infiltrates of CD4 + and CD8 + T eff cells that correlate with prolonged overall survival in PDAC patients (14,15,(21)(22)(23)(24)(25)(26). There is also evidence for ongoing anti-tumour immunity; Freed-Pastor et al identified a population of HLA-DR + Ki67 + CD57 -CD8 + T cellsindicative of an activated, proliferative phenotypethat are present in the majority of patients (27).…”

Section: Why Have Icis Proved Ineffective In the Context Of Pdac?mentioning

confidence: 99%

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Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

Smith,

Arbe-Barnes,

Shah

et al. 2024

Front. Immunol.

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The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (Tregs), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of Tregs has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating Tregs correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing Treg-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit Treg-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of Treg-targeted immunotherapies for PDAC.

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Section: Why Have Icis Proved Ineffective In the Context Of Pdac?mentioning

confidence: 85%

Section: Why Have Icis Proved Ineffective In the Context Of Pdac?mentioning

confidence: 99%

Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

Smith,

Arbe-Barnes,

Shah

et al. 2024

Front. Immunol.

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“…Furthermore, after characterising tumour infiltrating lymphocytes (TILs) in PDAC, we see that even though there is limited exhaustion in a subset of CD8 T cells, we observed that a significant number of CD4 and CD8 T cells were senescent 7,8 . Additionally, we see a activated Treg expressing checkpoints TIGIT, ICOS, CTLA4 and CD39 7,9 suggesting a strongly immunosuppressive microenvironment. This activation was determined by the high expression of the checkpoints TIGIT, ICOS, CTLA4 and CD39 7,9 .…”

Section: Introductionmentioning

confidence: 83%

“…Additionally, we see a activated Treg expressing checkpoints TIGIT, ICOS, CTLA4 and CD39 7,9 suggesting a strongly immunosuppressive microenvironment. This activation was determined by the high expression of the checkpoints TIGIT, ICOS, CTLA4 and CD39 7, 9 .…”

Section: Introductionmentioning

confidence: 99%

Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments

Sivakumar,

Jainarayanan,

Arbe-Barnes

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Understanding the multiple mechanisms by which the tumour evades immune control, and how these mechanisms may be disrupted is critical to developing targeted immunotherapies. Previous studies have shown that higher lymphocyte infiltration is associated with better survival, and here we investigated what mediates these differences. We performed a comprehensive analysis of PDAC-associated immune cells using single cell multi-omics coupled with re-analysis of public PDAC scRNA-seq datasets. We introduce novel single-cell and repertoire analyses that have uncoupled diverse roles and contributions of various immune cell populations within different tumour microenvironments (TMEs). They revealed clear distinctions in the clonal characteristics among different patient groups, provided valuable insights into the mechanisms of immune cell migration and tissue adaptation underlying these disparities. These results point to differential CD4 polarisation of intra-tumoural T cells, differential B cell differentiation, GC reactions, antigen presentation pathways, and distinct cell-cell communication between the myeloid-enriched and adaptive-enriched groups. Overall, we identified two major distinct themes for future immune intervention within PDAC patients between those with higher adaptive versus myeloid immune cell infiltration.

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“…For example, CellRank builds on RNA velocity and trajectory inference models (such as pseudotime) to predict fate potentials given the stochastic nature of fate decisions ( Lange et al, 2022 ). CellRank has been used to predict fate probabilities and reprogramming outcomes in several developmental systems ( Hersbach et al, 2022 ; Lange et al, 2022 ; Van Bruggen et al, 2022 ; Bono et al, 2023 ; Matsushita et al, 2023 ), whereas applications to cancer systems have mainly focused on trajectory inference for the immune compartment rather than cancer cells ( Xue et al, 2022 ; Friedrich et al, 2023 ; Jainarayanan et al, 2023 ). DeepVelo uses neural networks to learn transcriptomic dynamics, building a model that predicts trajectories, driver genes, and the effect of in silico perturbation on fate decisions ( Chen et al, 2022 ); however, this approach has not yet been applied to cancer systems.…”

Section: Modeling Plasticity In Epigenetic Landscapes Via Single-cell...mentioning

confidence: 99%

Quantifying cancer cell plasticity with gene regulatory networks and single-cell dynamics

Groves,

Quaranta

2023

Front. Netw. Physiol.

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Phenotypic plasticity of cancer cells can lead to complex cell state dynamics during tumor progression and acquired resistance. Highly plastic stem-like states may be inherently drug-resistant. Moreover, cell state dynamics in response to therapy allow a tumor to evade treatment. In both scenarios, quantifying plasticity is essential for identifying high-plasticity states or elucidating transition paths between states. Currently, methods to quantify plasticity tend to focus on 1) quantification of quasi-potential based on the underlying gene regulatory network dynamics of the system; or 2) inference of cell potency based on trajectory inference or lineage tracing in single-cell dynamics. Here, we explore both of these approaches and associated computational tools. We then discuss implications of each approach to plasticity metrics, and relevance to cancer treatment strategies.

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Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells

Cited by 3 publications

References 46 publications

Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments

Quantifying cancer cell plasticity with gene regulatory networks and single-cell dynamics

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