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Quantitative cell type specific immunopeptidome analysis during macrophage and tumor co-evolution reveals therapeutic MHC-I restricted peptides in glioblastoma

ABSTRACT: Glioblastoma treatment by immunotherapy is limited by the immunosuppresive tumor microenvironment, in part created by GBM associated macrophages. To uncover targetable MHC-I peptides for targeted immunotherapy, we performed cell type specific immunopeptidome analysis on primary macrophages and GBM tumor cells in a co-culture system to profile antigen presentation at the tumor:macrophage interface. Profiling the MHC-I restricted peptides revealed systematic antigen presentation alteration in both GBM tumors and macrophages during their co-evolution. We selected co-culture induced significantly altered peptides (CIVS peptides) which can serve as potential immunotherapy targets, and developed an mRNA vaccine encoding six selected CIVS peptides from GAMs and GBM tumor cells. Two doses of mRNA vaccination generated antigen specific immune response, significantly delayed GBM tumor growth, and in some cases eradicated tumor, demonstrating the translational potential of CIVS peptides as therapeutic targets for GBM/GAM targeting vaccines.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Neoplastic Cell, Cell Culture, Macrophage

DISEASE(S): Brain Glioblastoma Multiforme,Brain Cancer

SUBMITTER: Yufei Cui

LAB HEAD: Forest M.

PROVIDER: PXD057588 | Pride | 2025-09-03

REPOSITORIES: Pride

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			Action	DRS
	BMDM_KOline_coculture_CD45pos_ac1-9_40_F1-6_20230724.mzML	Mzml
	BMDM_KOline_coculture_CD45pos_ac1-9_40_F1-6_20230724.mzid.gz	Mzid
	BMDM_KOline_coculture_CD45pos_ac1-9_40_F1_20230723.raw	Raw
	BMDM_KOline_coculture_CD45pos_ac1-9_40_F2_20230723.raw	Raw
	BMDM_KOline_coculture_CD45pos_ac1-9_40_F3_20230723.raw	Raw

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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.

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Quantitative cell type specific immunopeptidome analysis during macrophage and tumor co-evolution reveals therapeutic MHC-I restricted peptides in glioblastoma

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