2020

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

Show abstract
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

Show abstract
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

Show abstract
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

Show abstract
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.