B cells and tertiary lymphoid structures promote immunotherapy response

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, Alexandria 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 E.; 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, D. Seshagiri; Krijgsman, Oscar; Rozeman, Elisa A.; Peeper, Daniel S.; Blank, Christian U.; Schumacher, Ton N.; Butterfield, Lisa H.; Zelazowska, Monika A.; McBride, Kevin M.; Kalluri, Raghu; Allison, James P.; Petitprez, Florent; Fridman, Wolf‐Herman; Hacohen, Nir; Rezvani, Katayoun; Sharma, Padmanee; Wang, Linghua; Wargo, Jennifer A.

doi:10.1038/s41586-019-1922-8

Cited by 1,788 publications

(1,625 citation statements)

References 61 publications

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“…T RH cells may therefore participate in the regulation of chronic lung disease development. Further, recent advances have suggested that the development of tertiary lymphoid structures consisting of CD4 + T and B cell clusters inside tumor effectively predicts patient responses to checkpoint blockade (anti-PD-1 and/or anti-CTLA4) therapies 81, 82, 83 . Given the transcriptional similarity of T RM cells and tumor infiltrating lymphocytes (TILs) 84 , it is possible that those T FH -like cells present inside those tertiary lymphoid structures within tumor also exhibit tissue-resident signatures (i.e.…”

Section: Discussionmentioning

confidence: 99%

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Son

Cheon

et al. 2020

Preprint

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32The roles of CD4 + T helper cells (TH) in shaping localized memory B and CD8 + T cell immunity 33 in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local 34 assistance for the optimal development of tissue-resident memory B (BRM) and CD8 + T (TRM) 35 cells following the resolution of primary influenza virus infection. We identify a population of 36 tissue-resident CD4 + TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell 37 features and mediate local help of CD4 + T cells to B and CD8 + T cells. Optimal TRH cell 38 formation requires lung B cells and transcription factors involved in TFH or TRM development. 39Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-40 21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population 41 that is specialized in assisting the development of mucosal protective B and CD8 + T cell 42 responses in situ.

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Section: Discussionmentioning

confidence: 99%

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Son

Cheon

et al. 2020

Preprint

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“…RNA is most often extracted from fresh frozen tissue. In most studies using laser microdissection, library preparation was performed on fresh frozen tissue (41,42) access to tumor samples is limited to core needle biopsies (44,45). The blocks we used were 3 to 10 years old and are representative of the material available in a clinical pathology biobank.…”

Section: Discussionmentioning

confidence: 99%

“…We questioned the abundance of different immune cell types from the expression profile with MCP-counter deconvolution (6), a well-established method that has been used to identify predictive biomarkers for response to immunotherapy (44). Spatial enrichment in specific immune cell subpopulations was variable across the seven cases of TNBC as confirmed by multispectral IHC.…”

Section: Discussionmentioning

confidence: 99%

Spatial transcriptomics of tumor microenvironment in formalin-fixed paraffin-embedded breast cancer

Romanens

Chaskar

Tille

et al. 2020

Preprint

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Tumor samples are conserved in clinical practice in formalin-fixed paraffin-embedded (FFPE) blocks. Formalin fixation chemically alters nucleic acids, rendering transcriptomic analysis challenging. RNA-sequencing is usually performed on tumor bulk, without distinction of cell subtypes or location. Here we describe the development of a robust method for RNA extraction and exome-capture RNA-sequencing of lasercapture microdissected tumor cells (TC) and stromal immune cells (TIL) based on their morphology. We applied this method on 7 tumor samples (surgical or core needle biopsy) of triple-negative breast cancer (TNBC) stored in FFPE blocks over 3-10 years.Unsupervised clustering and principal component analysis showed a clear separation between gene-expression profile of TIL and TC. TIL were enriched in markers of B cells (CD79B, PAX5 and BLNK ) and T cells (CD2, CD3D and CD8B) whereas tumor cells expressed epithelial markers (EPCAM, MUC1 and KRT8). Microenvironment cell populations-counter (MCP)-counter deconvolution showed an enrichment in adaptive immune cell signatures in microdissected TIL. Transcripts of immune checkpoints were differentially expressed in TIL and TC. We further validated our results by qRT-PCR and multispectral immunohistochemistry. In conclusion, we showed that combining laser-capture microdissection and RNA-sequencing on archived FFPE blocks is feasible and allows spatial transcriptional characterization of tumor microenvironment.

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“…Specific subtypes of B cells seem to be primarily responsible for the B cell triggered anti-tumour response 17,[25][26][27] . We therefore assessed whether the observed difference in NFϰB activation is B cell subtype specific.…”

Section: Igg+ Plasma Cells Show Reduced Nfϰb Activationmentioning

confidence: 99%

ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis

Griss

Viteri

Sidiropoulos

et al. 2020

Preprint

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Pathway analyses are key methods to analyse ‘omics experiments. Nevertheless, integrating data from different ‘omics technologies and different species still requires considerable bioinformatics knowledge.Here we present the novel ReactomeGSA resource for comparative pathway analyses of multi-omics datasets. ReactomeGSA can be used through Reactome’s existing web interface and the novel ReactomeGSA R Bioconductor package with explicit support for scRNA-seq data. Data from different species is automatically mapped to a common pathway space. Public data from ExpressionAtlas and Single Cell ExpressionAtlas can be directly integrated in the analysis. ReactomeGSA thereby greatly reduces the technical barrier for multi-omics, cross-species, comparative pathway analyses.We used ReactomeGSA to characterise the role of B cells in anti-tumour immunity. We compared B cell rich and poor human cancer samples from five TCGA transcriptomics and two CPTAC proteomics studies. There, B cell-rich lung adenocarcinoma samples lack the otherwise present activation through NFkappaB. This may be linked to the presence of a specific subset of tumour associated IgG+ plasma cells that lack NFkappaB activation in scRNA-seq data from human melanoma. This showcases how ReactomeGSA can derive novel biomedical insights by integrating large multi-omics datasets.

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B cells and tertiary lymphoid structures promote immunotherapy response

Cited by 1,788 publications

References 61 publications

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Spatial transcriptomics of tumor microenvironment in formalin-fixed paraffin-embedded breast cancer

ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis

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B cells and tertiary lymphoid structures promote immunotherapy response

Cited by 1,788 publications

References 61 publications

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

Spatial transcriptomics of tumor microenvironment in formalin-fixed paraffin-embedded breast cancer

ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis

Contact Info

Product

Resources

About

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses