331 research outputs found
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Empirical Reverse Engineering of Vaccine Neoantigens
No full textSince the advent of immunization, vaccines have been composed of natural antigens pulled from the proteome of the infectious agent. To pick potentially protective antigens, pathogens must be deeply studied to elucidate their life cycles, patterns of protein expression, and interactions with their hosts. This reliance on understanding pathogen biology requires the etiology of disease to be known, hampers the speed of vaccine development, and generates vaccines with curtailed efficacy. Infectious pandemics and the cancer epidemic provide unambiguous motivation for the creation of an agnostic platform to develop potent vaccines.Here, we outline our vaccine development approach to (1) characterize T-cell receptors (TCRs) responding to an insult, (2) perform antigen discovery for discovered TCRs, and (3) vaccinate with found, novel neoantigens. We hypothesize that novel, synthetic peptide ligands can effectively prime the same repertoire of na�ve T cells that clonally respond to infection. To find the optimal synthetic antigens, we designed a NFκB-driven, cell-based antigen discovery platform to interrogate TCRs with a diverse and streamlined pool of peptide antigens. Using our functional, unbiased method to screen for peptide ligands, we performed antigen discovery for known TCRs and novel TCRs from an in vivo cancer model. Our platform was specific, sensitive, and tunable in finding TCR-activating antigens. The system was able to successfully find cognate antigens for known TCRs. When performing antigen discovery for T cells resulting from an in vivo tumor model, our platform found antigens corresponding to known, expressed tumor antigens. Furthermore, we found that a streamlined peptide library can reduce peptide library complexity while still providing useful information on TCR-binding motifs. Our future directions include in vitro and in vivo testing with discovered neoantigens for known and novel TCRs.Overall, identifying TCRs and screening TCR-binding ligands can aid in the development of vaccines in the fields of infection, cancer, allergy, autoimmunity, and transplantation. Our long-term goal is to bring about a new method for developing effective antigens for vaccines by identifying peptides that stimulate discovered, insult-specific protective T cells. If successful, our approach will have a major impact on vaccinology: we enable the possibility of developing effective vaccines without having to identify the insult as an initial step, a major boon for emerging infections or epidemics of known or unknown etiology
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Enhancing Tumor-Infiltrating T cells with an Exclusive Fuel Source
No full textSolid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is a building block of cellulose, contains a β-1,4-glycosidic bond that cannot be hydrolyzed by animals (or their tumors), but fungal and bacterial organisms have evolved enzymes to catabolize cellobiose and use the resulting glucose. By equipping T cells with two proteins that enable import and hydrolysis of cellobiose, we demonstrate that supplementation of cellobiose during glucose withdrawal restores T cell cytokine production and cellular proliferation. Murine tumor growth is suppressed, and survival is prolonged. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. Beyond cancer, this approach could be used to answer questions about the regulation of glucose metabolism across many cell types, biological processes, and diseases
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Macromolecular structures of receptor-ligand complexes from developmental neurobiology and cancer biology
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Author Correction: AGREE-S: AGREE II extension for surgical interventions: appraisal instrument (Surgical Endoscopy, (2022), 36, 8, (5547-5558), 10.1007/s00464-022-09354-z)
No full textThis article was updated to correct Alessandro Montedori’s name. Collaborative authorship: The GAP Consortium: Yasser Sami Abdel Dayem, Luca Bertolaccini, Pablo Alonso- Coello, Elie Akl, Manish Chand, John J. Como, Gert J. de Borst, Salomone Di Saverio, Sameh Emile, Bang Wool Eom, Ramon Gorter, George Hanna, Kaisa Immonen, Quirino Lai, Nicolaas Lumen, Joseph L. Mathew, Alessandro Montendori, Martin Moya, Gianluca Pellino, Alvaro Sanabria, Athanasios Saratzis, Neil Smart, Dimitrios Stefanidis, Giovanni Zaninotto
Author Correction: AGREE-S: AGREE II extension for surgical interventions: appraisal instrument (Surgical Endoscopy, (2022), 36, 8, (5547-5558), 10.1007/s00464-022-09354-z)
No full textThis article was updated to correct Alessandro Montedori’s name. Collaborative authorship: The GAP Consortium: Yasser Sami Abdel Dayem, Luca Bertolaccini, Pablo Alonso- Coello, Elie Akl, Manish Chand, John J. Como, Gert J. de Borst, Salomone Di Saverio, Sameh Emile, Bang Wool Eom, Ramon Gorter, George Hanna, Kaisa Immonen, Quirino Lai, Nicolaas Lumen, Joseph L. Mathew, Alessandro Montendori, Martin Moya, Gianluca Pellino, Alvaro Sanabria, Athanasios Saratzis, Neil Smart, Dimitrios Stefanidis, Giovanni Zaninotto
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