B cells and tertiary lymphoid structures promote immunotherapy response,Nature

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B cells and tertiary lymphoid structures promote immunotherapy response
Nature ( IF 50.5 ) Pub Date : 2020-01-15 , DOI: 10.1038/s41586-019-1922-8
Beth A Helmink ₁ , Sangeetha M Reddy ₂ , Jianjun Gao ₃ , Shaojun Zhang ₄ , Rafet Basar ₅ , Rohit Thakur ₁ , Keren Yizhak ₆ , Moshe Sade-Feldman _{6,

7} , Jorge Blando ₈ , Guangchun Han ₄ , Vancheswaran Gopalakrishnan ₁ , Yuanxin Xi ₉ , Hao Zhao ₈ , Rodabe N Amaria ₁₀ , Hussein A Tawbi ₁₀ , Alex P Cogdill ₁ , Wenbin Liu ₈ , Valerie S LeBleu ₁₁ , Fernanda G Kugeratski ₁₁ , Sapna Patel ₁₀ , Michael A Davies ₁₀ , Patrick Hwu ₁₀ , Jeffrey E Lee ₁ , Jeffrey E Gershenwald ₁ , Anthony Lucci ₁ , Reetakshi Arora ₄ , Scott Woodman ₁₀ , Emily Z Keung ₁ , Pierre-Olivier Gaudreau ₁ , Alexandre Reuben ₁₂ , Christine N Spencer ₁₃ , Elizabeth M Burton ₁ , Lauren E Haydu ₁ , Alexander J Lazar _{4,

14,

15} , Roberta Zapassodi ₁₆ , Courtney W Hudgens ₁₄ , Deborah A Ledesma ₁₄ , SuFey Ong ₁₇ , Michael Bailey ₁₇ , Sarah Warren ₁₇ , Disha Rao ₁₈ , Oscar Krijgsman ₁₈ , Elisa A Rozeman ₁₈ , Daniel Peeper ₁₈ , Christian U Blank ₁₈ , Ton N Schumacher ₁₈ , Lisa H Butterfield ₁₉ , Monika A Zelazowska ₂₀ , Kevin M McBride ₂₀ , Raghu Kalluri ₁₁ , James Allison ₈ , Florent Petitprez _{21,

22,

23} , Wolf Herman Fridman _{21,

22} , Catherine Sautès-Fridman _{21,

22} , Nir Hacohen _{6,

7} , Katayoun Rezvani ₅ , Padmanee Sharma _{3,

8} , Michael T Tetzlaff _{14,

15} , Linghua Wang ₄ , Jennifer A Wargo _{1,

4}

Affiliation

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Broad Institute of the Massachusetts Institute of Technology, Boston, MA, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Thoracic / Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nanostring Technologies, Seattle, WA, USA.
Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Departments of Medicine, Surgery, Immunology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
INSERM, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France.
University Paris Descartes Paris 5, Sorbonne Paris Cite, Centre de Recherche des Cordeliers, Paris, France.
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers^{1,2,3,4,5,6,7,8,9,10} 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^{11,12,13,14,15}, 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.

中文翻译：

B细胞和三级淋巴结构促进免疫治疗反应

免疫检查点阻断 (ICB) 治疗彻底改变了癌症治疗。到目前为止，预测性生物标志物^{1、2、3、4、5、6、7、8、9、10}和增强临床反应的策略主要集中在 T 细胞区室。然而，其他免疫亚群也可能有助于抗肿瘤免疫^{11,12,13,14,15}，尽管这些在 ICB 治疗中的研究较少¹⁶。先前在黑色素瘤患者中进行的新辅助 ICB 试验通过靶向表达谱显示¹⁷B细胞特征在对治疗有反应的患者与无反应患者的肿瘤中富集。在此基础上，我们进行了批量 RNA 测序，发现 B 细胞标记是应答者与非应答者肿瘤中表达差异最大的基因。我们的发现通过计算方法得到证实（MCP-counter ¹⁸）来估计这个和另外两个 ICB 治疗的队列（黑色素瘤和肾细胞癌患者）中的免疫和基质组成。组织学评估强调了 B 细胞在三级淋巴结构内的定位。我们通过大量和单细胞 RNA 测序评估了 B 细胞的潜在功能贡献，这证明了 B 细胞在应答者中的克隆扩增和独特的功能状态。质谱流式细胞术显示，转换记忆 B 细胞在应答者的肿瘤中富集。总之，这些数据提供了对 B 细胞和三级淋巴结构在 ICB 治疗反应中的潜在作用的见解，并对生物标志物和治疗靶点的开发产生了影响。

更新日期：2020-01-15

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