The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition

Risbjerg, Rasmus Strøm; Hansen, Mie Vennize; Sørensen, Anne Sofie; Kragstrup, Tue Wenzel

doi:10.1186/s40164-020-00167-1

Cited by 10 publications

(7 citation statements)

References 6 publications

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“…There has been at least one report of decreased IRAEs in the setting for B cell-depleting therapy (i.e. for lymphoma) (Risbjerg et al 2020); however, given our observation of irColitis in a patient depleted of B cells and the few differences in tissue B cells seen in our data, B cell depletion is expected to have little impact on irColitis incidence. Unlike in IBD, we observed no skewing from IgA to IgG plasma B cells.…”

Section: Discussioncontrasting

confidence: 61%

Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

Thomas

Slowikowski

Manakongtreecheep

et al. 2021

Preprint

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Therapeutic blockade of co-inhibitory immune receptors PD-1 and CTLA-4 has revolutionized oncology, but treatments are limited by immune-related adverse events (IRAEs). IRAE Colitis (irColitis) is the most common, severe IRAE affecting up to 25% of patients on dual PD-1 and CTLA-4 inhibition. Here, we present a systems biology approach to define the cell populations and transcriptional programs driving irColitis. We collected paired colon mucosal biopsy and blood specimens from 13 patients with irColitis, 8 healthy individuals, and 8 controls on immune checkpoint inhibitors (ICIs), and analyzed them with single-cell/nuclei RNA sequencing with paired TCR and BCR sequencing, multispectral fluorescence microscopy, and secreted factor analysis (Luminex). We profiled 299,407 cells from tissue and blood and identified 105 cell subsets that revealed significant tissue remodeling in active disease. Colon mucosal immune populations were dominated by tissue-resident memory (Trm) ITGAE-expressing CD8 T cells representing a phenotypic spectrum defined by gene programs associated with T cell activation, cytotoxicity, cycling, and exhaustion. CD8 Trm and effector CD4 T cells upregulated type 17 immune programs (IL17A, IL26) and Tfh-like programs (CXCL13, PDCD1). We also identified for the first time an increased abundance of two KLRG1 and ITGB2-expressing CD8 T cell populations with circulatory cell markers, including a GZMK Trm-like population and a CX3CR1 population that is predicted to be intravascular. These two populations were more abundant in irColitis patients treated with dual PD-1/CTLA-4 inhibition than those receiving anti-PD-1 monotherapy. They also had significant TCR sharing with PBMCs, suggesting a circulatory origin. In irColitis we observed significant epithelial turnover marked by fewer LGR5-expressing stem cells, more transit amplifying cells, and upregulation of apoptotic and DNA-sensing programs such as the cGAS-STING pathway. Mature epithelial cells with top crypt genes upregulated interferon-stimulated pathways, CD274 (PD-L1), anti-microbial genes, and MHC-class II genes, and downregulated aquaporin and solute-carrier gene families, likely contributing to epithelial cell damage and absorptive dysfunction. Mesenchymal remodeling was defined by increased endothelial cells, both in irColitis patients and specifically in patients on dual PD-1/CTLA-4 blockade. Cell-cell communication analysis identified putative receptor-ligand pairs that recruit CD8 T cells from blood to inflamed endothelium and positive feedback loops such as the CXCR3 chemokine system that retain cells in tissue. This study highlights the cellular and molecular drivers underlying irColitis and provides new insights into the role of CTLA-4 and PD-1 signaling in maintaining CD8 Trm homeostasis, regulating CD8 T recruitment from blood, and promoting epithelial-immune crosstalk critical to gastrointestinal immune tolerance and intestinal barrier function.

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Section: Discussioncontrasting

confidence: 61%

Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

Thomas

Slowikowski

Manakongtreecheep

et al. 2021

Preprint

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“…Genetic predispositions to certain irAEs have been observed with variants of the human leukocyte antigen (HLA) gene, such as HLA-DRB1*11:01 and pruritus (odds ratio [OR] = 4.53, p < 0.01) as well as HLA-DQB1*03:01 and colitis (OR = 3.94, p = 0.017). The role of B lymphocytes in development of irAEs has been deduced from clinical studies: Patients on B cell-depleting therapies had zero cases of thyroiditis amongst 29 patients treated with pidilizumab, a PD-1 inhibitor, for follicular lymphoma [62], whereas this irAE typically occurs in 6-10% of patients with intact B cells. The pro-inflammatory cytokine interleukin-17 (IL-17), produced by T helper 17 (Th17) lymphocytes, appear to have a role in the development of ICI-induced colitis.…”

Section: Immune-related Adverse Events Secondary To Icimentioning

confidence: 99%

The gut microbiome, immune check point inhibition and immune-related adverse events in non-small cell lung cancer

Bredin¹,

Naidoo

2022

Cancer Metastasis Rev

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Systemic treatment options for patients with lung cancer have expanded in recent years, with a number of immunotherapeutic strategies now in our treatment armamentarium. Toxicity of and resistance to treatment hold a major stake in lung cancer morbidity and mortality. Herein, we summarise the background, current evidence and potential mechanisms underlying the role of the commensal gut microbiota in immunotherapy outcomes such as response and toxicity in patients with non-small cell lung cancer (NSCLC).

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“…A role for B cells, beside T cells, in ICI-related autoimmunity has recently been suggested by data linking circulating B cells to different types of IRAEs (43) and by the occurrence of organspecific antibodies in patients developing IRAEs (44). Moreover, targeting B cells with the anti-CD20 antibody rituximab reduced the frequency of ICI-related hypothyroidism (44,45), and clinical trials that combine B cell depletion with ICI treatment to prevent IRAEs are ongoing (46), giving credence to the notion of B cell involvement in ICI-IRAE.…”

Section: Discussionmentioning

confidence: 99%

Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint‐Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor–Induced Inflammatory Arthritis

Gatto

Bjursten

Jonsson

et al. 2023

Arthritis & Rheumatology

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Objective To investigate potential associations between B cell–related immunologic changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICIs). Methods Patients who developed ICI‐induced IA (ICI‐IA) and patients who did not develop immune‐related adverse events (non‐IRAE) after receiving ICIs to treat metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI‐IA occurrence and at different time points during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, anti–citrullinated protein antibodies, and antibodies against joint‐related proteins were measured. Results Proportions of CD19+ B cells were higher in patients with ICI‐IA (n = 7) compared to patients with non‐IRAE (n = 15) (median 11.7% [interquartile range (IQR) 9.7–16.2%] versus 8.1% [IQR 5.7–11.0%]; P = 0.03). The proportion and absolute numbers of transitional CD19+CD10+CD24highCD38high B cells were increased in patients with ICI‐IA compared to non‐IRAE patients (median 8.1% [IQR 4.9–12.1%] versus 3.6% [IQR 1.9–4.9%]; median 10.7 cells/μl [IQR 8.9–19.6] versus 4.4 cells/μl [IQR 2.3–6.6]; P < 0.01 for both). In addition, higher levels of transitional B cells were associated with development of ICI‐IA (odds ratio 2.25 [95% confidence interval 1.03–4.9], P = 0.04). Transitional B cells increased before the onset of overt ICI‐IA and decreased between the active and quiescent stages of ICI‐IA (P = 0.02). Autoantibodies to type II collagen epitopes were detected in up to 43% of ICI‐IA patients compared to none of the non‐IRAE patients (P = 0.02). Conclusion Development of ICI‐IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint‐related proteins. Monitoring of B cell–driven abnormalities upon ICI treatment may help earlier recognition of ICI‐IA.

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The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition

Cited by 10 publications

References 6 publications

Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

The gut microbiome, immune check point inhibition and immune-related adverse events in non-small cell lung cancer

Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint‐Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor–Induced Inflammatory Arthritis

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