Role of B cells in immune‐related adverse events following checkpoint blockade

Dhodapkar, Kavita M.; Duffy, Alyssa; Dhodapkar, Madhav V.

doi:10.1111/imr.13238

Cited by 5 publications

(5 citation statements)

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“…In ltration of tissues with activated T cells is considered to be a hallmark of irAEs [30]. Moreover, activation of B cells, humoral immunity, and/or tertiary lymphoid structures also participate in the development of irAEs [31]. The activation of autoreactive lymphocytes is a core mechanism of irAEs.…”

Section: Discussionmentioning

confidence: 99%

Cancer Cachexia-related Monocytic MDSCs Impair T-cell Negative Selection and Predict Immune-related Adverse Events

Li,

Wei,

Huang

et al. 2024

Preprint

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Background Cancer cachexia is prevalent in multiple cancers and is associated with chemotherapy toxicity. However, data on the relationship between immune-related adverse events (irAEs) and cachexia are limited. Methods A murine model of orthotopic hepatocellular carcinoma (HCC) with cachexia was constructed to determine the effect of T-cell infiltration in multiple tumor-free organs on irAEs occurrence. Single-cell sequencing of thymic stromal cells was conducted. Patients with advanced cancers receiving anti-PD-1/L1 antibody treatment were followed up to investigate the relationship between cachexia and irAEs. Results Inflammatory cells infiltrated multiple tumor-free organs in cachexic HCC but not in non-cachexic mice. Immunofluorescence revealed that these infiltrating cells included CD4+ and CD8+ T-cells. Morphological assessment and hematoxylin-eosin staining confirmed thymus atrophy in cachexic HCC mice. Single-cell sequencing of thymic stromal cells showed fewer medullary thymic epithelial cells (mTECs) II and III in the thymus of cachexic mice than in those of non-cachexic mice. Aire downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs. T cells from cachexic HCC mice induced inflammation and T cell infiltration in multiple organs of tumor-free mice in an organ-specific manner. After administration of anti-mouse PD-1 antibody, the incidence of inflammation in multiple organs was much higher in cachexic HCC mice as well as tumor free mice transferred with T cells from cachexic HCC mice. Thymic monocytic myeloid-derived suppressor cells (M-MDSCs) enriched in cachexic HCC mice, evidenced by flow cytometer and immunofluorescence analyses. M-MDSCs infiltrated the thymus in cachexic mice with cancer. Cachexia-related M-MDSCs induced mTEC from tumor-free mice apoptosis through nitric oxide production in vitro. M-MDSCs transfer induced infiltration of inflammatory cells in multiple organs and thymus involution of tumor free mice without decreasing their weights. Sixty-four patients with advanced cancer receiving anti-PD-1/L1 antibody treatment were included in this study. Patients with irAEs displayed higher levels of circulating M-MDSCs than those without irAEs. Moreover, patients with cachexia (BMI < 20 kg/m2 or weight loss ≥ 5% over the past 6 months) had higher M-MDSC levels. Patients with high M-MDSC levels and low BMI or weight loss ≥ 5% experienced more irAEs (HR 2.333, 95% CI 1.231–4.423). Conclusions M-MDSCs induced mTEC apoptosis through nitric oxide production in cachexic mice with cancer, impairing T-cell negative selection and leading to autoimmune T-cell infiltration in tumor-free organs. Cancer cachexia-related M-MDSCs are potential predictive biomarkers of irAEs in patients with advanced cancer.

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Section: Discussionmentioning

confidence: 99%

Cancer Cachexia-related Monocytic MDSCs Impair T-cell Negative Selection and Predict Immune-related Adverse Events

Li,

Wei,

Huang

et al. 2024

Preprint

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“…As these adverse events may be more agent specific rather than specific to the underlying tumor, it could suggest activation of preexisting autoreactive T and B cells. Mechanisms proposed include release of inhibition by regulatory T cells resulting in greater T:B cell cross talk, and direct activation of Tbet+ B cells ( 96 ). Importantly, “CD21lo” B cells are increased in patients with melanoma who are treated with anti-CTLA4 or anti-PD1 plus anti-CTLA4, and these cells were transcriptionally suggestive of ABCs.…”

Section: Role In Paraneoplastic Syndromes Autoimmunity and Checkpoint...mentioning

confidence: 99%

Clonal redemption of B cells in cancer

McCaw,

Lofftus,

Crompton

2023

Front. Immunol.

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Potentially self-reactive B cells constitute a large portion of the peripheral B cell repertoire in both mice and humans. Maintenance of autoreactive B cell populations could conceivably be detrimental to the host but their conservation throughout evolution suggests performance of a critical and beneficial immune function. We discuss herein how the process of clonal redemption may provide insight to preservation of an autoreactive B cell pool in the context of infection and autoimmunity. Clonal redemption refers to additional recombination or hypermutation events decreasing affinity for self-antigen, while increasing affinity for foreign antigens. We then review findings in murine models and human patients to consider whether clonal redemption may be able to provide tumor antigen-specific B cells and how this may or may not predispose patients to autoimmunity.

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“…Kavita Dhodapkar, Alyssa Duffy, and Madhav Dhodapkar discuss how the use of immune checkpoint inhibitor therapy can impact B‐cell tolerance and drive alterations in the B‐cell compartments 48 . Their review explores the potential involvement of humoral immunity, and the role of specific B‐cell subsets and autoantibodies in driving the irAE pathogenesis associated with the use of ICI.…”

Section: Introductionmentioning

confidence: 99%

“…Kavita Dhodapkar, Alyssa Duffy, and Madhav Dhodapkar discuss how the use of immune checkpoint inhibitor therapy can impact B-cell tolerance and drive alterations in the B-cell compartments. 48 Their review explores the potential involvement of humoral immunity, and the role of specific B-cell subsets and autoantibodies in driving the irAE pathogenesis associated with the use of ICI. They also highlight the need to invest more resources in investigating the cross talk between T and B cells that drives the activation of pathogenic B cells, contributing to the development of irAEs.…”

mentioning

confidence: 99%