γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival

Gherardin, Nicholas A.; Waldeck, Kelly; Caneborg, Alex; Martelotto, Luciano G.; Balachander, Shiva; Zethoven, Magnus; Petrone, Pasquale; Pattison, Andrew; Wilmott, James S.; Quiñones-Parra, Sergio M.; Rossello, Fernando; Posner, Atara; Wong, Annie; Weppler, Alison M.; Shannon, Kerwin F.; Hong, Angela; Ferguson, Peter M.; Jakrot, Valerie; Raleigh, Jeanette; Hatzimihalis, Athena; Neeson, Paul J.; Deleso, Paolo; Johnston, Melissa P.; Chua, Margaret; Becker, Juergen C.; Sandhu, Shahneen; McArthur, Grant A.; Gill, Anthony J.; Scolyer, Richard A.; Hicks, Rodney J.; Godfrey, Dale I.; Tothill, Richard W.

doi:10.1158/2326-6066.cir-20-0817

Cited by 34 publications

(28 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To the best of our knowledge, detecting γδ T cells from αβ T cells is limited utilizing scRNA-seq, in both human and animal studies, as detection of γδ T cells requires not only large sample sizes but also a signature of γδ T cells combined with NK and T CD8 + -discarding genes (Pizzolato, 2019). To overcome this, we can detect T cell lineages via ow cytometric assessment or single-cell T-cell Receptor (TCR) sequencing in future studies (Lee, M, et al, 2020, Gherardin, N, et al, 2021. Understanding T cell lineages will reveal crucial insight into the pathology of TBI, as γδ T cells have been known to promote the in ammatory responses in the CNS (Wo, J, et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Microglia and infiltrating T-cells adopt long-term, age-specific, transcriptional changes after traumatic brain injury

Chen¹,

Islam²,

Timken³

et al. 2022

Preprint

View full text Add to dashboard Cite

Introduction: Traumatic brain injury (TBI) afflicts over 3 million Americans every year. Patients over 65 years of age suffer increased mortality as well as greater long-term neurocognitive and neuropsychiatric morbidity compared to younger adults. Microglia, the resident macrophages of the brain, are complicit in both. Our published and preliminary data have demonstrated a significant age-effect in which aged microglia are more prone to adopt a constitutively activated state associated with worse neurocognitive and neuropsychiatric outcomes. Therefore, we hypothesized that aged microglia would fail to return to a homeostatic state after TBI but instead adopt a long-term injury-associated state within the brain of aged mice as compared to young-adult mice after TBI. Methods: Young-adult (14-weeks) and aged (80-weeks) C57BL/6 mice underwent TBI via controlled cortical impact vs. sham injury. We utilized single-cell RNA sequencing to examine age-associated cellular responses after TBI. Four months post-TBI or sham injury, brains were harvested, and CD45+ cells (N=4,000 cells) were isolated via florescence-activated cell sorting. cDNA libraries were prepared via the 10x Genomics Chromium Single Cell 3' Reagent Kit, followed by sequencing on a HiSeq 4000 instrument. The raw data were processed using the Cell Ranger pipeline mapped to the mm10 mouse reference genome and Seurat following standard workflow. Seurat and GOrilla were used for downstream clustering, differential gene expression, and pathway analysis. All cell types were annotated using canonical markers and top expressed genes. ProjecTILs was additionally used to interpret T cell states. Results: Microglia from young-adult and aged mice have distinct transcriptional profiles pre-injury and markedly different transcriptional responses post-injury compared to young-adult mice. Pre-injury, aged mice demonstrated a disproportionate immune cell infiltration, including T cells, as compared to young-adult mice (aged versus young: 45.5% vs. 14.5%). Post-injury, the disparity was amplified with a proportional decrease in homeostatic microglia and greater increased infiltrating T cells compared to young-adult mice (Microglia: 27.5% vs. 71%; T cell: 45.5% vs. 4.5%). Of note, aged mice post-injury had a subpopulation of unique, age-specific, immune-inflammatory microglia resembling gene profiles of neurodegenerative disease-associated microglia (DAM) with enriched pathways involved in leukocyte recruitment and Alzheimer’s disease pathogenesis (FDR < 0.05). Contrastingly, post-injury, aged mice demonstrate a heterogenous T-cell infiltration with gene profiles corresponding to CD8 effector memory, CD8 native-like, CD4, and double-negative T cells (75.9%, 2.5%, 12.9%, and 8.6%, respectively) and enriched pathways including tau protein binding, macromolecule synthesis, and cytokine-mediated signaling pathways (FDR < 0.05). Conclusion: We hypothesized that aged microglia would fail to return to a homeostatic state after TBI and adopt a long-term, injury-associated state within the brain of aged mice as compared to young-adult mice after TBI. In particular, our data suggest an age-dependent reduction of homeostatic microglia post-injury yet an upregulation in a unique microglial subpopulation with a distinct immuno-inflammatory profile. Furthermore, aged subjects demonstrated a markedly disproportionate inflammatory infiltrate after TBI predominated by the presence of CD8+ T cells. In addition, post-injury, brain trauma reorganized the T cell milieu, especially CD8 effector memory T cells, via upregulating genes associated with macromolecule biosynthesis process and negative regulation of neuronal death, possibly linking TBI with its long-term sequelae and complications. Taken together, our data showed that age-specific gene signature changes in the T-cell infiltrates and the microglial subpopulation contributes to increased vulnerability of the aged brain to TBI. Age should be an a priori consideration in future TBI clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Microglia and infiltrating T-cells adopt long-term, age-specific, transcriptional changes after traumatic brain injury

Chen¹,

Islam²,

Timken³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…82 Merkel cell carcinoma lesions profiled with scRNA-seq showed a unique γδ T-cell subpopulation with a 13-gene pro-inflammatory signature, which could serve as a prognostic biomarker. 83…”

Section: Cutaneous Neoplasmsmentioning

confidence: 99%

Single‐cell transcriptomics in human skin research: available technologies, technical considerations and disease applications

Theocharidis

Tekkela

Veves

et al. 2022

Experimental Dermatology

View full text Add to dashboard Cite

The human skin is defined by a multilayer architecture based on diverse cell populations of mainly keratinocytes and fibroblasts, as well as various immune cells, melanocytes, adipocytes and endothelial cells that orchestrate events leading to wound repair of pathogenic infections and exposure to ultraviolet radiation and toxic compounds. 1 The transcriptomic profile of skin can provide information on gene expression, non-coding regulatory elements and gene splicing, and therefore shed light on skin physiology and pathology. Earlier approaches such as bulk RNA-seq and microarrays provided information about the average transcriptome status

show abstract

“…γδ T lymphocytes have potential prognostic value in various human cancers [ 85 , 86 ]. Although there is no hard evidence that this is also the case in CLL, there are several observations suggesting it.…”

Section: Vδ1 Cells Are More Cytotoxic Towards Cll Clones Than Vδ2mentioning

confidence: 99%

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

Zarobkiewicz

Bojarska‐Junak

2022

Cells

View full text Add to dashboard Cite

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults. It is the clonal expansion of B cells expressing CD19 and CD5. Despite significant progress in treatment, CLL is still incurable. γδ T cells comprise an important subset of the cytotoxic T cells. Although γδ T cells in CLL are dysfunctional, they still can possibly be used for immunotherapy. The current paper reviews our understanding of γδ T lymphocytes in CLL.

show abstract

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival

Cited by 34 publications

References 50 publications

Microglia and infiltrating T-cells adopt long-term, age-specific, transcriptional changes after traumatic brain injury

Microglia and infiltrating T-cells adopt long-term, age-specific, transcriptional changes after traumatic brain injury

Single‐cell transcriptomics in human skin research: available technologies, technical considerations and disease applications

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

Contact Info

Product

Resources

About