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 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 and Jennifer A. Wargo ()
Additional contact information
Beth A. Helmink: The University of Texas MD Anderson Cancer Center
Sangeetha M. Reddy: The University of Texas MD Anderson Cancer Center
Jianjun Gao: The University of Texas MD Anderson Cancer Center
Shaojun Zhang: The University of Texas MD Anderson Cancer Center
Rafet Basar: The University of Texas MD Anderson Cancer Center
Rohit Thakur: The University of Texas MD Anderson Cancer Center
Keren Yizhak: Massachusetts General Hospital Cancer Center
Moshe Sade-Feldman: Massachusetts General Hospital Cancer Center
Jorge Blando: The University of Texas MD Anderson Cancer Center
Guangchun Han: The University of Texas MD Anderson Cancer Center
Vancheswaran Gopalakrishnan: The University of Texas MD Anderson Cancer Center
Yuanxin Xi: The University of Texas MD Anderson Cancer Center
Hao Zhao: The University of Texas MD Anderson Cancer Center
Rodabe N. Amaria: The University of Texas MD Anderson Cancer Center
Hussein A. Tawbi: The University of Texas MD Anderson Cancer Center
Alex P. Cogdill: The University of Texas MD Anderson Cancer Center
Wenbin Liu: The University of Texas MD Anderson Cancer Center
Valerie S. LeBleu: The University of Texas MD Anderson Cancer Center
Fernanda G. Kugeratski: The University of Texas MD Anderson Cancer Center
Sapna Patel: The University of Texas MD Anderson Cancer Center
Michael A. Davies: The University of Texas MD Anderson Cancer Center
Patrick Hwu: The University of Texas MD Anderson Cancer Center
Jeffrey E. Lee: The University of Texas MD Anderson Cancer Center
Jeffrey E. Gershenwald: The University of Texas MD Anderson Cancer Center
Anthony Lucci: The University of Texas MD Anderson Cancer Center
Reetakshi Arora: The University of Texas MD Anderson Cancer Center
Scott Woodman: The University of Texas MD Anderson Cancer Center
Emily Z. Keung: The University of Texas MD Anderson Cancer Center
Pierre-Olivier Gaudreau: The University of Texas MD Anderson Cancer Center
Alexandre Reuben: The University of Texas MD Anderson Cancer Center
Christine N. Spencer: Parker Institute for Cancer Immunotherapy
Elizabeth M. Burton: The University of Texas MD Anderson Cancer Center
Lauren E. Haydu: The University of Texas MD Anderson Cancer Center
Alexander J. Lazar: The University of Texas MD Anderson Cancer Center
Roberta Zapassodi: Memorial Sloan Kettering Cancer Center
Courtney W. Hudgens: The University of Texas MD Anderson Cancer Center
Deborah A. Ledesma: The University of Texas MD Anderson Cancer Center
SuFey Ong: Nanostring Technologies
Michael Bailey: Nanostring Technologies
Sarah Warren: Nanostring Technologies
Disha Rao: The Netherlands Cancer Institute
Oscar Krijgsman: The Netherlands Cancer Institute
Elisa A. Rozeman: The Netherlands Cancer Institute
Daniel Peeper: The Netherlands Cancer Institute
Christian U. Blank: The Netherlands Cancer Institute
Ton N. Schumacher: The Netherlands Cancer Institute
Lisa H. Butterfield: University of Pittsburgh
Monika A. Zelazowska: The University of Texas MD Anderson Cancer Center
Kevin M. McBride: The University of Texas MD Anderson Cancer Center
Raghu Kalluri: The University of Texas MD Anderson Cancer Center
James Allison: The University of Texas MD Anderson Cancer Center
Florent Petitprez: Immune Control and Escape
Wolf Herman Fridman: Immune Control and Escape
Catherine Sautès-Fridman: Immune Control and Escape
Nir Hacohen: Massachusetts General Hospital Cancer Center
Katayoun Rezvani: The University of Texas MD Anderson Cancer Center
Padmanee Sharma: The University of Texas MD Anderson Cancer Center
Michael T. Tetzlaff: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center

Nature, 2020, vol. 577, issue 7791, 549-555

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-019-1922-8

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