Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8
            <sup>+</sup>
            T cell clone size and cytotoxicity

Watson, Robert; Tong, Orion; Ca, Taylor; Sharma, Piyush Kumar; Aires, Alba Verge de los; Mahé, Elise A.; Ruffieux, Hélène; Nassiri, Isar; Middleton, Mark R.; Fairfax, Benjamin P.

doi:10.1126/sciimmunol.abj8825

Cited by 47 publications

(67 citation statements)

References 59 publications

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“…De novo arthralgia, inflammatory arthritis, tendinitis/tenosynovitis, enthesitis and (poly-)myalgia have been reported in about 20% of ICI patients in clinical trials, with a large variation in prevalence due to differing criteria and awareness of these side effects 4 5. Intriguingly, the development of ICI-induced irAE has been associated with a better survival and clinical outcome,6–8 including patients with rheumatic irAEs 9–11. However, severe irAEs may force clinicians to terminate ICI therapy due to ICI-irAE-associated mortality for 0.5%–1.5% of patients 12.…”

Section: Introductionmentioning

confidence: 99%

Distinct immune-effector and metabolic profile of CD8⁺T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

et al. 2022

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ObjectivesRheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI therapy improves CD8+ T cell (CD8) function, but CD8 contributes to chronic inflammation in autoimmune arthritis (AA). Thus, we investigated whether immune functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients.MethodsPeripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing 13C-labelled glucose with and without tofacitinib or infliximab. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules and inhibition of tumour cell growth were quantified.ResultsCD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838.ConclusionsOur study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has a distinct immune-effector and metabolic profile from those that remain irAE free. This specific irAE profile overlaps with the one observed in CD8 from AA patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs.

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Section: Introductionmentioning

confidence: 99%

Distinct immune-effector and metabolic profile of CD8⁺T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

et al. 2022

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“…This population shared a strong cytotoxic profile that mirrors those seen in clonally expanded peripheral blood CD8 populations in metastatic melanoma 18 . The clonal populations were largest in the three responding patients in our cohort and clonal size of expanded CD8+ T-cell clones has been shown to predict response to immune checkpoint blockade in metastatic melanoma 18,47 .…”

Section: Discussionmentioning

confidence: 63%

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

Ramchurren

Fling

et al. 2022

Preprint

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The PD-1 inhibitor pembrolizumab is effective in treating Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sézary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment by single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sézary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sézary T cells. Pembrolizumab modulated Sézary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sézary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sézary syndrome.

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“…A recent study in humans used paired scRNA seq and scTCR seq to analyze CD4 + T cells and CD8 + T cells across 21 cancer types (including melanoma and breast, gastric, pancreatic, kidney, and esophageal cancers) from 316 patients; the study identified two major developmental trajectories that contributed to T cell exhaustion across multiple tumor types, based on transcriptional information [32]. Additionally, scTCR seq has been useful to inform mechanisms of response following PD-1-based immunotherapy in cancer patients [30,[36][37][38][39][40][41], as later discussed. While these studies have shown that scTCR seq data can be promising for focused analyses on T cell populations of interest, there are limitations to this method (Boxes 1-3).…”

Section: Trends In Immunologymentioning

confidence: 99%

TCR-sequencing in cancer and autoimmunity: barcodes and beyond

Pauken¹,

Lagattuta²,

Lu³

et al. 2022

Trends in Immunology

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Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8 ⁺ T cell clone size and cytotoxicity

Abstract: The cytotoxicity and clone size of CD8 + T cell pretreatment are prognostic for immune checkpoint blockade.

Cited by 47 publications

References 59 publications

Distinct immune-effector and metabolic profile of CD8⁺T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

Distinct immune-effector and metabolic profile of CD8⁺T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

TCR-sequencing in cancer and autoimmunity: barcodes and beyond

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Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8 + T cell clone size and cytotoxicity

Abstract: The cytotoxicity and clone size of CD8 + T cell pretreatment are prognostic for immune checkpoint blockade.

Cited by 47 publications

References 59 publications

Distinct immune-effector and metabolic profile of CD8+T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

Distinct immune-effector and metabolic profile of CD8+T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

TCR-sequencing in cancer and autoimmunity: barcodes and beyond

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Product

Resources

About

Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8 ⁺ T cell clone size and cytotoxicity

Distinct immune-effector and metabolic profile of CD8⁺T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

Distinct immune-effector and metabolic profile of CD8⁺T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors