The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

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One Sentence Summary:The Yellow Fever vaccine induces a CD8 T stem cell-like memory subset that preserves a high degree of "Naïveness" and is stably maintained for over two decades in humans. with no studies beyond five years post-vaccination. 7Hereby, we investigated 41 vaccinees, spanning 0.27 to 35 years after vaccination. YF-8 specific CD8 T cells were readily detected in almost all donors (38/41), with frequencies 9 decreasing with time. As previously described, effector cells dominated the response early 10 after vaccination. We detected a population of Naïve-like YF-specific CD8 T cells that was 11 stably maintained for over 25 years and was capable of self-renewal ex vivo. In-depth 12 analyses of markers and genome-wide mRNA profiling showed that Naïve-like YF-specific 13 CD8 T cells in vaccinees: i) were distinct from genuine Naïve cells in unvaccinated donors 14 ii) resembled the recently described stem cell-like memory subset (Tscm), and iii) amongst 15 all differentiated subsets, had profiles closest to the Naïve. Our findings reveal that CD8 16 Tscm are efficiently induced by a vaccine in humans, persist for decades and preserve a 17 particularly high degree of "Naïveness". This supports YF vaccination as an optimal 18 mechanistic model for the study of long-lasting memory CD8 T cells in humans.

With the advent of combined immunotherapies, personalized dendritic cell (DC)-based vaccination could integrate the current standard of care for the treatment of a large variety of tumors. Due to their proficiency at antigen presentation, DC are key coordinators of the innate and adaptive immune system, and have critical roles in the induction of antitumor immunity. However, despite proven immunogenicity and favorable safety profiles, DC-based immunotherapies have not succeeded at inducing significant objective clinical responses. Emerging data suggest that the combination of DC-based vaccination with other cancer therapies may fully unleash the potential of DC-based cancer vaccines and improve patient survival. In this review, we discuss the recent efforts to develop innovative personalized DC-based vaccines and their use in combined therapies, with a particular focus on ovarian cancer and the promising results of mutanome-based personalized immunotherapies.