Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+) tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens

Conceptual design of the Cryogenic Electrical Feedboxes and the Superconducting Links of LHC

Powering the superconducting magnets of the LHC arcs and long straight sections is performed with more than 1000 electrical terminals supplying currents ranging from 120 A to 13’000 A and distributed in 44 cryogenic electrical feedboxes (DFB). Where space in the LHC tunnel is sufficient, the magnets are powered by locally installed cryogenic electrical feedboxes. Where there is no space for a DFB, the current will be supplied to the magnets by superconducting links (DSL) connecting the DFBs to the magnets on distances varying from 76 m to 510 m

Design and Validation of Conditional Ligands for HLA-B*08:01, HLA-B*15:01, HLA-B*35:01, and HLA-B*44:05

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide-MHC complexes

The promiscuous nature of T-cell receptors (TCRs) allows T cells to recognize a large variety of pathogens, but makes it challenging to understand and control T-cell recognition(1). Existing technologies provide limited information about the key requirements for T-cell recognition and the ability of TCRs to cross-recognize structurally related elements(2,3). Here we present a ‘one-pot’ strategy for determining the interactions that govern TCR recognition of peptide–major histocompatibility complex (pMHC). We measured the relative affinities of TCRs to libraries of barcoded peptide–MHC variants and applied this knowledge to understand the recognition motif, here termed the TCR fingerprint. The TCR fingerprints of 16 different TCRs were identified and used to predict and validate cross-recognized peptides from the human proteome. The identified fingerprints differed among TCRs recognizing the same epitope, demonstrating the value of this strategy for understanding T-cell interactions and assessing potential cross-recognition before selection of TCRs for clinical development