B cells and tertiary lymphoid structures promote immunotherapy response.

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.

• Authors: Beth A Helmink, Sangeetha M Reddy, Jianjun Gao, Shaojun Zhang, Rafet Basar, Rohit Thakur, Keren Yizhak, Moshe Sade-Feldman, Jorge Blando, Guangchun Han, Vancheswaran Gopalakrishnan, Yuanxin Xi, Hao Zhao, Rodabe N Amaria, Hussein A Tawbi, Alex P Cogdill, Wenbin Liu, Valerie S LeBleu, Fernanda G Kugeratski, Sapna Patel, Michael A Davies, Patrick Hwu, Jeffrey E Lee, Jeffrey E Gershenwald, Anthony Lucci, Reetakshi Arora, Scott Woodman, Emily Z Keung, Pierre-Olivier Gaudreau, Alexandre Reuben, Christine N Spencer, Elizabeth M Burton, Lauren E Haydu, Alexander J Lazar, Roberta Zapassodi, Courtney W Hudgens, Deborah A Ledesma, SuFey Ong, Michael Bailey, Sarah Warren, Disha Rao, Oscar Krijgsman, Elisa A Rozeman, Daniel Peeper, Christian U Blank, Ton N Schumacher, Lisa H Butterfield, Monika A Zelazowska, Kevin M McBride, Raghu Kalluri, James Allison, Florent Petitprez, Wolf Herman Fridman, Catherine Sautès-Fridman, Nir Hacohen, Katayoun Rezvani, Padmanee Sharma, Michael T Tetzlaff, Linghua Wang, Jennifer A Wargo
• Journal: Nature (Nature) Vol. 577 Issue 7791 Pg. 549-555 (01 2020) ISSN: 1476-4687 [Electronic] England
• PMID: 31942075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Biomarkers, Tumor
• Receptors, Immunologic

Topics

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