B cells and tertiary lymphoid structures promote immunotherapy response

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 PatelMichael 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, Su Fey 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

Research output: Contribution to journalArticle

93 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)549-555
Number of pages7
JournalNature
Volume577
Issue number7791
DOIs
StatePublished - Jan 23 2020

ASJC Scopus subject areas

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    Helmink, B. A., Reddy, S. M., Gao, J., Zhang, S., Basar, R., Thakur, R., Yizhak, K., Sade-Feldman, M., Blando, J., Han, G., Gopalakrishnan, V., Xi, Y., Zhao, H., Amaria, R. N., Tawbi, H. A., Cogdill, A. P., Liu, W., LeBleu, V. S., Kugeratski, F. G., ... Wargo, J. A. (2020). B cells and tertiary lymphoid structures promote immunotherapy response. Nature, 577(7791), 549-555. https://doi.org/10.1038/s41586-019-1922-8