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Neoantigens, also known as tumor-specific antigens, is a class of HLA-bound peptides generated by tumor-specific mutations. They are not present in normal tissues, thus can be used as biomarkers differentiating cancer cells from normal cells. Compared to those non-mutated self-antigens, neoantigens could be recognized as non-self by the host immune system and are thus attractive targets for immunotherapies with potentially increased efficacy, specificity, and safety. It has been shown that recognition of these individual-specific neoantigens opens a new door for cancer immunotherapy.
The immunogenicity of neoantigens leading to T cell response has long been demonstrated in human. Recently, independent clinical studies provided solid evidence that neoantigen-based cancer vaccines could be developed to elicit potent neoantigen-specific T cell responses against late stage melanoma with remarkable safety and efficacy. These and other recent advances (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036114/table/T1/?report=objectonly) have triggered the enthusiasm in pursuing cancer vaccines against neoantigens.
However, one of the key challenges in the development of neoantigen-based therapies is that immunogenic neoantigens are rare and difficult to predict. And the TCR signaling is complex as antigen binding does not uniformly lead to functional TCR signaling. Thus, accurate predictive algorithm and validation tools are need to be optimized for accurate prediction of binding peptides and reliable selection of highly immunogenic neoepitopes. Classic approaches for understanding T cell specificity and possible neoantigen rely on readouts of T cell function, which include assays for cytotoxicity, cytokine release, and proliferation in the presence of candidate's antigens, augmented by peptide-MHC tetramers for antigen-specific populations and others. However, these are primarily useful for predetermined sets of 10-100 s of antigens but are unsuitable at genome scale.
Several other approaches have been taken to map unknown T cell specificities and neoantigens. A recent approach uses display of peptides as single-chain fusions to MHC on the surface of target cells. T cell binding to cognate antigen results in trogoctyosis or activation of a synthetic signaling molecule, enabling the isolation of recognized target cells. Another method uses display of genetically encoded random peptides covalently attached to MHC molecules on the surface of yeast and use soluble TCRs to pan the yeast library for peptide-MHC binding. Notably, neither yeast display nor single-chain approaches require endogenous processing of antigens nor functional activation of T cells, which leaves uncertainty as to whether the identified antigens are physiologically meaningful in vivo.
To overcome such obstacle, a new platform named T-Scan was developed. It is a cell-based pooled screen, high-throughput, genome-wide platform for the systematic identification of antigens by T cells. This platform harness lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules, correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. The antigen recognition by TCRs is monitored through a fluorescent reporter of activity in the target cells, hereby characterize the reactivity of a tumor-derived TCR.
(image resource from https://www.sciencedirect.com/science/article/pii/S0092867419307743#undfig1)
Genscript's Peptide for T-scan and neoantigen service
Peptides can be used as single stimulants, pools or libraries, or as part of peptide/major histocompatibility complexes (MHC) for direct T-cell receptor staining and related therapeutic application. For stimulating T cells, peptides must be bound to MHC molecules. Thus the quality of synthetic peptide is crucial on this contribution. Based on theoretic considerations, published data, feedback from customers and our over 10-years experience, we have set a strict quality standards for neoantigen peptides, including peptide purity, TFA control, TFA removal, endotoxin control, endotoxin removal and so on. These parameters contribute to effective stimulating while reduce interference factors. Besides, considering the neoantigen peptide hydrophobicity, our solubility test facilitate customer to choose proper solvent hereby ensuring the usability. These considering service attracts more clients to cooperate with Genscript, covering from fundamental researches to preclinical trials.
First Author Conversations Podcast
Anna Pasetto, Ph.D., Karolinska Institutet
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