Bystander B cells rapidly acquire antigen receptors from activated B cells by membrane transfer: a novel mechanism for enhancing specific antigen presentation

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

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Role of Newly Synthesized MHC Class II Molecules in Antigen-Specific Antigen Presentation by B cells

Immunobiology ◽

10.1016/s0171-2985(11)80154-3 ◽

1995 ◽

Vol 193 (1) ◽

pp. 42-58 ◽

Cited By ~ 4

Author(s):

Takehiro Kokuho ◽

Hideo Nariuchi ◽

Yuichi Gyotoku ◽

Terutaka Kakiuchi

Keyword(s):

B Cells ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Specific Antigen ◽

Class Ii ◽

Mhc Class Ii Molecules

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Surface immunoglobulins mediate efficient transport of antigen to lysosomal compartments resulting in enhanced specific antigen presentation by B cells

European Journal of Immunology ◽

10.1002/eji.1830241127 ◽

1994 ◽

Vol 24 (11) ◽

pp. 2755-2760 ◽

Cited By ~ 4

Author(s):

Ko-Jiunn Liu ◽

Vandana S. Parikh ◽

Philip W. Tucker ◽

Byung S. Kim

Keyword(s):

B Cells ◽

Antigen Presentation ◽

Specific Antigen ◽

Surface Immunoglobulins ◽

Efficient Transport

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P06.05 Endogenous T-cell responses to ten major cancer testis antigens are frequent in esophago-gastric adenocarcinoma and antigen-specific T cells can be expanded using CD40-activated B cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.39 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A21.1-A21

Author(s):

M Thelen ◽

M Garcia-Marquez ◽

J Lehmann ◽

D Keller ◽

E Preugszat ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Antigen Presentation ◽

T Cell Responses ◽

Cell Abundance ◽

Cell Responses ◽

Cancer Testis Antigens ◽

Cancer Testis ◽

Activated B Cells

BackgroundTumor-associated antigens (TAAs) and especially cancer testis antigens (CTAs) are classical tumor-specific targets for immunotherapies. As TAAs are shared between patients, strategies aiming to exploit these targets are scalable and potentially applicable across different types of cancer. Loss of target antigens and other mechanisms of immune escape have limited the success of CTA-directed immunotherapy. CAR T cells and other highly effective cellular therapies have renewed the interest in TAAs. Especially combined targeting of multiple antigens appears highly promising as recently shown in lymphoma. In our study, we aimed to characterize CTA-expression patterns and their impact on endogenous T-cell responses, T-cell abundance and antigen-presentation in esophago-gastric adenocarcinoma (EGA).Materials and Methods41 treatment-naïve EGA patients were included in our study. RNA of tumor and patient-matched healthy tissue was isolated and used for NanoString based RNA expression analysis of 26 CTAs and 25 genes associated with antigen-presentation. Based on CTA expression, 10 peptide pools were selected and co-cultured with peripheral blood mononuclear cells (PBMCs, n=21) to determine cellular anti-tumor immune responses in a FluoroSpot assay. T-cell abundance was assessed using immunohistochemistry (CD3, CD8) and digital image analyses of tumor area and invasive margin. Autologous CD40 activated B cells were used to expand antigen-specific T cells using peptide pools of CTAs.ResultsNanoString analysis revealed pronounced differences regarding CTA expression, with CEP55 and MAGEA3/6 showing strong expression, while NY-ESO-1 or MAGEA1 were only weakly expressed. 68.3% (28/41) of the patients showed expression of ≥ 5/10 analyzed TAAs simultaneously. In line with the frequent expression, 75.0% of the patients showed a cellular response against at least one of the TAAs. T-cell responses were most frequently detected to Survivin and NY-ESO-1 (65.0% and 52.6% of patients, respectively), while only 20.0% responded to CEP55 or TTK peptide pools. Overall, 6/20 patients showed cellular responses against ≥5 TAAs simultaneously. We found a strong correlation of T-cell abundance and antigen-presentation. In addition, patients with a high Immune-Score showed increased TAA expression. Finally, we demonstrate feasibility of TAA-specific T-cell expansion using CD40 activated B cells as potential strategy to induce or enhance TAA immune responses in EGA.ConclusionsOur study highlights the importance of TAAs in EGA. The identified antigens are highly relevant for immunomonitoring of clinical trials and as targets for immunotherapy. Personalized immunotherapeutic strategies targeting EGA-specific or even patient specific TAAs appear highly promising in this challenging disease.Disclosure InformationM. Thelen: None. M. Garcia-Marquez: None. J. Lehmann: None. D. Keller: None. E. Preugszat: None. M. von Bergwelt-Baildon: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Astellas, Roche, MSD. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; BMS. F. Consultant/Advisory Board; Modest; BMS. H.A. Schlößer: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astra Zeneca.

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Exploiting B Cell Transfer for Cancer Therapy: Engineered B Cells to Eradicate Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22189991 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9991

Author(s):

Audrey Page ◽

Julie Hubert ◽

Floriane Fusil ◽

François-Loïc Cosset

Keyword(s):

B Cells ◽

B Cell ◽

Antigen Presentation ◽

Tumor Antigens ◽

Plasma Cells ◽

Ex Vivo ◽

Treatment Options ◽

Specific Antigen ◽

Cell Receptor ◽

Defined Culture

Nowadays, cancers still represent a significant health burden, accounting for around 10 million deaths per year, due to ageing populations and inefficient treatments for some refractory cancers. Immunotherapy strategies that modulate the patient’s immune system have emerged as good treatment options. Among them, the adoptive transfer of B cells selected ex vivo showed promising results, with a reduction in tumor growth in several cancer mouse models, often associated with antitumoral immune responses. Aside from the benefits of their intrinsic properties, including antigen presentation, antibody secretion, homing and long-term persistence, B cells can be modified prior to reinfusion to increase their therapeutic role. For instance, B cells have been modified mainly to boost their immuno-stimulatory activation potential by forcing the expression of costimulatory ligands using defined culture conditions or gene insertion. Moreover, tumor-specific antigen presentation by infused B cells has been increased by ex vivo antigen loading (peptides, RNA, DNA, virus) or by the sorting/ engineering of B cells with a B cell receptor specific to tumor antigens. Editing of the BCR also rewires B cell specificity toward tumor antigens, and may trigger, upon antigen recognition, the secretion of antitumor antibodies by differentiated plasma cells that can then be recognized by other immune components or cells involved in tumor clearance by antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity for example. With the expansion of gene editing methodologies, new strategies to reprogram immune cells with whole synthetic circuits are being explored: modified B cells can sense disease-specific biomarkers and, in response, trigger the expression of therapeutic molecules, such as molecules that counteract the tumoral immunosuppressive microenvironment. Such strategies remain in their infancy for implementation in B cells, but are likely to expand in the coming years.

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