B cells and tertiary lymphoid structures promote immunotherapy response

• Published in: Nature (London) Vol. 577; no. 7791; pp. 549 - 555
• Main Authors: Helmink, Beth A., Reddy, Sangeetha M., Gao, Jianjun, Zhang, Shaojun, Basar, Rafet, Thakur, Rohit, Yizhak, Keren, Sade-Feldman, Moshe, Blando, Jorge, Han, Guangchun, Gopalakrishnan, Vancheswaran, Xi, Yuanxin, Zhao, Hao, Amaria, Rodabe N., Tawbi, Hussein A., Cogdill, Alex P., Liu, Wenbin, LeBleu, Valerie S., Kugeratski, Fernanda G., Patel, Sapna, Davies, Michael A., Hwu, Patrick, Lee, Jeffrey E., Gershenwald, Jeffrey E., Lucci, Anthony, Arora, Reetakshi, Woodman, Scott, Keung, Emily Z., Gaudreau, Pierre-Olivier, Reuben, Alexandre, Spencer, Christine N., Burton, Elizabeth M., Haydu, Lauren E., Lazar, Alexander J., Zapassodi, Roberta, Hudgens, Courtney W., Ledesma, Deborah A., Ong, SuFey, Bailey, Michael, Warren, Sarah, Rao, Disha, Krijgsman, Oscar, Rozeman, Elisa A., Peeper, Daniel, Blank, Christian U., Schumacher, Ton N., Butterfield, Lisa H., Zelazowska, Monika A., McBride, Kevin M., Kalluri, Raghu, Allison, James, Petitprez, Florent, Fridman, Wolf Herman, Sautès-Fridman, Catherine, Hacohen, Nir, Rezvani, Katayoun, Sharma, Padmanee, Tetzlaff, Michael T., Wang, Linghua, Wargo, Jennifer A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2020; Nature Publishing Group
• Subjects: 13/31; 13/51; 14/63; 38/39; 38/91; 631/67/1059/2325; 631/67/1813/1634; 692/53/2422; B cells; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomarkers; Biomarkers, Tumor - analysis; Cancer; Cancer therapies; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - surgery; Care and treatment; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - immunology; Clone Cells - cytology; Clone Cells - immunology; Clone Cells - metabolism; Computer applications; Cytometry; Dendritic Cells, Follicular - cytology; Dendritic Cells, Follicular - immunology; Gene expression; Gene Expression Regulation, Neoplastic; Gene sequencing; Humanities and Social Sciences; Humans; Immune checkpoint; Immunologic Memory - immunology; Immunological memory; Immunotherapy; Kidney cancer; Life Sciences; Localization; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoid tissue; Mass Spectrometry; Melanoma; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Melanoma - surgery; Memory cells; Metastasis; Methods; multidisciplinary; Neoplasm Metastasis - genetics; Patient outcomes; Patients; Phenotype; Physiological aspects; Prognosis; Receptors, Immunologic - immunology; Renal cell carcinoma; Ribonucleic acid; RNA; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Tertiary Lymphoid Structures - immunology; Therapeutic applications; Transcriptome; Tumors; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-1922-8

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers 1 – 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 immunity 11 – 15 , although these have been less well-studied in ICB treatment 16 . A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling 17 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-counter 18 ) 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. Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.