B cells and tertiary lymphoid structures promote immunotherapy response

Nature. 2020 Jan;577(7791):549-555. doi: 10.1038/s41586-019-1922-8. Epub 2020 Jan 15.

Abstract

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Biomarkers, Tumor / analysis
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / immunology*
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / surgery
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / immunology
  • Clone Cells / cytology
  • Clone Cells / immunology
  • Clone Cells / metabolism
  • Dendritic Cells, Follicular / cytology
  • Dendritic Cells, Follicular / immunology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunologic Memory / immunology
  • Immunotherapy*
  • Mass Spectrometry
  • Melanoma / drug therapy*
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / surgery
  • Neoplasm Metastasis / genetics
  • Phenotype
  • Prognosis
  • RNA-Seq
  • Receptors, Immunologic / immunology
  • Single-Cell Analysis
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Tertiary Lymphoid Structures / immunology*
  • Transcriptome

Substances

  • Biomarkers, Tumor
  • Receptors, Immunologic