Dataset Information

B cell Lymphomas present Immunoglobulin Neoantigens

ABSTRACT: Immunoglobulin gene rearrangement and somatic hypermutation have the potential to create neoantigens in non-Hodgkin B cell lymphoma. However, the presentation of these putative immunoglobulin neoantigens by B cell lymphomas has not been proven. We used MHC immunoprecipitation followed by liquid chromatography and tandem mass spectrometry (LC-MS/MS) to define antigens presented by follicular lymphomas (FL), chronic lymphocytic leukemias (CLL), diffuse large B cell lymphoma (DLBCL) and mantle cell lymphomas (MCL). We found presentation of the clonal immunoglobulin molecule, including neoantigens by both class I and class II MHC, though more commonly in class II MHC. To determine whether B cell activation could promote presentation of immunoglobulin neoantigens, we used a toll-like receptor 9 (TLR9) agonists to upregulate expression of MHC-II. This resulted in enhanced class II MHC presentation of the immunoglobulin variable region including neoantigens. These findings demonstrate that immunoglobulin neoantigens are presented across most subtypes of B cell lymphomas. Activation of lymphoma cells to upregulate antigen presentation boosts presentation of immunoglobulin neoantigens and represents a strategy for augmenting lymphoma immunotherapies.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Peripheral Blood Lymphocyte

DISEASE(S): Chronic Lymphocytic Leukemia,Follicular Lymphoma,Mantle Cell Lymphoma

SUBMITTER: Niclas Olsson

LAB HEAD: Joshua E Elias

PROVIDER: PXD010808 | Pride | 2019-01-07

REPOSITORIES: Pride

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B-cell lymphomas present immunoglobulin neoantigens.

Khodadoust Michael S MS Olsson Niclas N Chen Binbin B Sworder Brian B Shree Tanaya T Liu Chih Long CL Zhang Lichao L Czerwinski Debra K DK Davis Mark M MM Levy Ronald R Elias Joshua E JE Alizadeh Ash A AA

Blood 20181213 8

PMID: 30545830

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Project description:All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) can convey non-self antigens derived from pathogens or mutations to amount T-cell responses. Alterations in tumor-specific antigens – particularly mutation-bearing peptides (neoantigens) presented by MHC — can serve as potent substrates for anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring interferon gamma (IFN-γ) induced alterations to antigen presentation, using a lymphoma cell line. IFN-γ treatment resulted in a set of differentially expressed proteins (2 % of all quantified proteins) including components of antigen presentation machinery or interferon signaling pathways. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells antigen repertoires. Accordingly, by surveying immunopeptides, distinct peptide repertoires were exclusively observed in the IFN-γ induced samples. Furthermore, an additional set of presented peptides distinguished control and the IFN-γ samples by their altered relative abundances including neoantigens. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance should help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.

			Action	DRS
	Combined_CLL002_MHC1.csv	Csv
	Combined_CLL002_MHC2.csv	Csv
	Combined_CLL003_MHC1.csv	Csv
	Combined_CLL003_MHC2.csv	Csv
	Combined_FLMS001_MHC1.csv	Csv