479 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. Here we show that tumor-associated B cells (TAB) are vital to tumor associated inflammation. In human melanoma, TAB are located at the invasive tumor-stroma margin arguing for a preferentially cell contact-independent communication with tumor cells. We therefore exposed in vitro peripheral blood- and melanoma-derived B cells to conditioned medium from autologous melanoma cells. In proteomics and RNA-seq data, we observed induction of several pro- and anti-inflammatory factors and differentiation towards a plasmablast-like phenotype. We could identify this B cell phenotype as a distinct B cell cluster in public scRNA-seq data as well as by 7 color multiplex immunostaining of human melanoma samples. RNA-seq and multiplex immunostaining data also revealed that depletion of TAB by anti-CD20 immunotherapy of metastatic melanoma patients led to a pronounced decrease in tumor inflammation signatures and CD8+ T cell numbers, in line with scRNA-seq data on expression of T cell chemoattractants CCL5, CCL4, CCL28 in plasmablast-like TAB. The potential clinical implications of our observations are demonstrated in two independent large-scale whole-tissue (sc)RNA-seq datasets. Here, the frequency of plasmablast-like TAB in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade. Consistently, in a surrogate assay of T cell activation, MCM-induced B cells significantly increased the activation of PD-1-expressing Jurkat T cells by PD-1 blockade. Together, our data argue that tumor-associated B cells orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.