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.

Project description:Despite their remarkable success, the effectiveness of COVID-19 mRNA vaccines is notably diminished in organ transplant patients. Here, we employed a multi-omics approach to elucidate the immunological state at baseline and following SARS-CoV-2 mRNA vaccination of lung transplant (LTX) patients compared to healthy controls (HC). Our analysis revealed a baseline immune profile in LTX patients that mirrors the immune alterations observed in severe COVID-19 cases and sepsis. This profile is characterized by: (i) elevated pro-inflammatory cytokines in plasma, notably high levels of EN-RAGE and IL-6; (ii) reduced expression of HLA-DR on blood monocytes and dendritic cells (DCs); (iii) diminished cytokine production by blood monocytes and DCs in response to toll-like receptor (TLR) activation; (iv) increased plasma concentrations of microbial products. In addition to these alterations, single-cell RNA-seq analysis revealed 4 transcriptionally distinct clusters of classical monocytes in HC, with a striking enrichment of a unique classical monocyte cluster in LTX patients, differing from the predominant classical monocytes in HC, marked by heightened expression of the S100A family and reduced expression of genes related to cytokine production and antigen presentation. Following vaccination, LTX patients displayed a reduced magnitude and breadth of binding and neutralizing antibody responses, and impaired memory B and T cell responses. Furthermore, there was a blunted innate immune response to vaccination, evidenced by decreased transcriptional signatures linked to antigen presentation, dendritic cell activation, interferon and monocytes at the single-cell level. Integrative multiscale, multiresponse network (MMRN) analysis revealed an inverse correlation between the distinctive baseline immunological state observed in LTX patients and the adaptive immune responses to vaccines. These findings underscore the distinct immunological profile of lung transplant recipients, providing insights into their immunosuppressed condition and reduced immune responses to vaccines.

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Neoadjuvant CD40 agonism remodels the tumor immune microenvironment in locally advanced esophageal/gastroesophageal junction cancer [scRNA-seq]

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