2020

Salomon N, Vascotto F, Selmi A, Vormehr M, Quinkhardt J, Bukur T, Schrörs B, Löwer M, Diken M, Türeci Ö, Sahin U, Kreiter S. (2020) A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice. Oncoimmunology.  9:1771925. 

DOI

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Antigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compartments and selective expression in resident antigen-presenting cells.  We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependent manner by an RNA-LPX vaccine that encodes CD4+ T cell-recognized neoantigens (CD4 neoantigen vaccine).  Whereas CD8+ T cells induced by LRT alone were primarily directed against the immunodominant gp70 antigen, mice treated with LRT plus the CD4 neoantigen vaccine rejected gp70-negative tumors and were protected from rechallenge with these tumors, indicating a potent poly-antigenic CD8+ T cell response and T cell memory.  In the spleens of CD4 neoantigen-vaccinated mice, we found a high number of activated, poly-functional, Th1-like CD4+ T cells against ME1, the immunodominant CD4 neoantigen within the poly-neoantigen vaccine.  LRT itself strongly increased CD8+ T cell numbers and clonal expansion.  However, tumor infiltrates of mice treated with CD4 neoantigen vaccine/LRT, as compared to LRT alone, displayed a higher fraction of activated gp70-specific CD8+ T cells, lower PD-1/LAG-3 expression and contained ME1-specific IFNγ+ CD4+ T cells capable of providing cognate help.  CD4 neoantigen vaccine/LRT treatment followed by anti-CTLA-4 antibody therapy further enhanced the efficacy with complete remission of gp70-negative CT26 tumors and survival of all mice.  Our data highlight the power of combining synergistic modes of action and warrants further exploration of the presented treatment schema.

 

Roldán D, Grimmler M, Hartmann C, Hubich-Rau S, Beiβert T, Paret C, Cagna G, Rohde C, Wöll S, Koslowski M, Türeci O, Sahin U. (2020) PLAC1 is essential for FGF7/FGFRIIIb-induced Akt-mediated cancer cell proliferation. Oncotarget. 11:1862-1875.

DOI

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PLAC1 (placenta enriched 1) is a mammalian trophoblast-specific protein. Aberrant expression of PLAC1 is observed in various human cancers, where it is involved in the motility, migration, and invasion of tumor cells, which are associated with the phosphoinositide 3-kinase (PI3K)/AKT pathway. We previously demonstrated that AKT activation mediates the downstream effects of PLAC1; however, the molecular mechanisms of PLAC1-induced AKT-mediated tumor-related processes are unclear. We studied human choriocarcinoma and breast cancer cell lines to explore the localization and receptor-ligand interactions, as well as the downstream effects of PLAC1. We show secretion and adherence of PLAC1 to the extracellular matrix, where it forms a trimeric complex with fibroblast growth factor 7 (FGF7) and its receptor, FGF receptor 2 IIIb (FGFR2IIIb). We further show that PLAC1 signaling via FGFR2IIIb activates AKT phosphorylation in cancer cell lines. As the FGF pathway is of major interest in anticancer therapeutic strategies, these data further promote PLAC1 as a promising anticancer drug target.

 

Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H. (2020) OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nat. Comm. 11(1):1487.

DOI, PMID

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Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.

 

Holtsträter C, Schrörs B, Bukur T, Löwer M. (2020) Bioinformatics for Cancer Immunotherapy. In: Methods Mol Biol.  2120:1-9.  Springer.

DOI, PMID

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Our immune system plays a key role in health and disease as it is capable of responding to foreign antigens as well as acquired antigens from cancer cells. Latter are caused by somatic mutations, the so-called neoepitopes, and might be recognized by T cells if they are presented by HLA molecules on the surface of cancer cells. Personalized mutanome vaccines are a class of customized immunotherapies, which is dependent on the detection of individual cancer-specific tumor mutations and neoepitope (i.e., prediction, followed by a rational vaccine design, before on-demand production. The development of next generation sequencing (NGS) technologies and bioinformatic tools allows a large-scale analysis of each parameter involved in this process. Here, we provide an overview of the bioinformatic aspects involved in the design of personalized, neoantigen-based vaccines, including the detection of mutations and the subsequent prediction of potential epitopes, as well as methods for associated biomarker research, such as high-throughput sequencing of T-cell receptors (TCRs), followed by data analysis and the bioinformatics quantification of immune cell infiltration in cancer samples.

 

Reinhard K, Rengstl B, Oehm P, Michel K, Billmeier A, Hayduk N, Klein O, Kuna K, Ouchan Y, Wöll S, Christ E, Weber D, Suchan M, Bukur T, Birtel M, Jahndel V, Mroz K, Hobohm K, Kranz L, Diken M, Kühlcke K, Türeci Ö, Sahin U. (2020) An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science. 367:446-453.

DOI, PMID

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Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet their application for solid tumors has challenges that include limited cancer-specific targets and non-persistence of adoptively transferred CAR-T cells. Here we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors, and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident dendritic cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at sub-therapeutic CAR-T cell doses.

 

Vormehr M, Diken M, Türeci Ö, Sahin U, Kreiter S. (2020) Personalized Neo-Epitope Vaccines for Cancer Treatment. In: Theobald M. (eds) Current Immunotherapeutic Strategies in Cancer. Recent Results in Cancer Research, 214:153-167. Springer.  

DOI, PMID

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After more than a century of efforts to establish cancer immunotherapy in clinical practice, the advent of checkpoint inhibition (CPI) therapy was a critical breakthrough toward this direction (Hodi et al. in Cell Rep 13(2):412–424, 2010; Wolchok et al. in N Engl J Med 369(2):122–133, 2013; Herbst et al. in Nature 515(7528):563–567, 2014; Tumeh et al. in Nature 515(7528):568–571, 2014). Further, CPIs shifted the focus from long studied shared tumor-associated antigens to mutated ones. As cancer is caused by mutations in somatic cells, the concept to utilize these correlates of ‘foreignness’ to enable recognition and lysis of the cancer cell by T cell immunity seems an obvious thing to do.