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B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma.

ABSTRACT: Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanomas where plasmablast-like cells also express T cell-recruiting chemokines CCL3, CCL4, CCL5. Depletion of B cells in melanoma patients by anti-CD20 immunotherapy decreases tumor associated inflammation and CD8+ T cell numbers. Plasmablast-like cells also increase PD-1+ T cell activation through anti-PD-1 blockade in vitro and their frequency in pretherapy melanomas predicts response and survival to immune checkpoint blockade. Tumor associated B cells therefore orchestrate and sustain melanoma inflammation and may represent a predictor for survival and response to immune checkpoint blockade therapy.

SUBMITTER: Griss J

PROVIDER: S-EPMC6744450 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma.

Griss Johannes J Bauer Wolfgang W Wagner Christine C Simon Martin M Chen Minyi M Grabmeier-Pfistershammer Katharina K Maurer-Granofszky Margarita M Roka Florian F Penz Thomas T Bock Christoph C Zhang Gao G Herlyn Meenhard M Glatz Katharina K Läubli Heinz H Mertz Kirsten D KD Petzelbauer Peter P Wiesner Thomas T Hartl Markus M Pickl Winfried F WF Somasundaram Rajasekharan R Steinberger Peter P Wagner Stephan N SN

Nature communications 20190913 1

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanoma ...[more]

PMID: 31519915

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Project description:BackgroundImmune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB.MethodsPre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch.ResultsTwo natural GMB clusters with distinct community compositions were identified from the analysis of 16S rRNA data (R2 = 0.16, p < 0.001). In Cox-proportional hazard modeling, these two clusters showed a near 7-fold differential risk for developing irAEs within 1 year of initiating treatment (HR = 6.89 [95% CI: 1.33-35.58]). Using shotgun metagenomics, we further identified 37 bacterial strains differentially expressed between the risk groups, with specific dominance of Bacteroides dorei within the high-risk GMB cluster and Bacteroides vulgatus in the low-risk cluster. The high-risk cluster also appeared to have elevated expression of several functional pathways, including those associated with adenosine metabolism (all FDR < 0.05). A sub-analysis of samples (n = 10 participants) at baseline and 6 and 12 weeks after the start of treatment revealed that the microbiome remained stable over the course of treatment (R2 = 0.88, p < 0.001).ConclusionsWe identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.

Dataset Information

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma.

Publications

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma.

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