Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy

Dolton, Garry; Rius, Cristina; Wall, Aaron; Szomolay, Barbara; Bianchi, Valentina; Galloway, Sarah A. E.; Hasan, Md. Faruk; Morin, Théo; Caillaud, Marine E.; Thomas, Hannah; Theaker, Sarah M.; Tan, Li Rong; Fuller, Anna; Topley, Katie; Legut, Mateusz; Attaf, Meriem; Hopkins, Jade R.; Behiry, Enas M.; Zabkiewicz, Joanna; Alvares, Caroline; Lloyd, Alun G.; Rogers, Amber; Henley, Peter; Fegan, Christopher; Ottmann, Oliver G.; Man, Stephen; Crowther, Michael D.; Donia, Marco; Svane, Inge Marie; Cole, David K.; Brown, Paul E.; Rizkallah, P.J.; Sewell, Andrew K.

doi:10.1016/j.cell.2023.06.020

Cited by 35 publications

(22 citation statements)

References 73 publications

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“…To further explore the underlying mechanism of TCR cross-reactivity, we applied EPACT to predict the interaction conformation between a cancer-reactive MEL8 TCR and three tumor-associated epitopes in the context of HLA-A*02:01 47 . The TCR clone was derived from a stage IV malignant melanoma patient with successful tumor-infiltrating lymphocyte (TIL) therapy 70 .…”

Section: Resultsmentioning

confidence: 99%

“…EPACT significantly reduced the prediction errors for nearly all the residue pairs compared to the state-of-the-art method TEIM-Res. Specifically, EPACT reconstructed the CDR3β binding mode (with minor prediction errors) around the central Threonine (T), connecting four consecutive peptide amino acids (G4, I5, G6, and I7) 47 by one hydrogen bond and van der Waals interactions. The consensus on core interacting sites also suggested the peptide motif contributing to the molecular mimicry.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to state-of-the-art performance in distinguishing pairing TCRs of given pMHC complex from decoys, EPACT also exhibits outstanding capacity in illuminating the residue-level interactions within the CDR-epitope interface. We further apply EPACT to SARS-CoV-2 epitope-specific TCR clonotypes under diverse infection and vaccination conditions 45 as well as structure-driven TCR cross-reactivity instances in autoimmune diseases 46 and cancer immunotherapies 47 . Our analyses demonstrate the application potential of EPACT in accelerating the development of TCR-based diagnostics and immunotherapies for infectious diseases and cancers.…”

Section: Introductionmentioning

confidence: 99%

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Epitope-anchored contrastive transfer learning for paired CD8⁺T cell receptor-antigen recognition

Zhang,

Wang,

Jiang

et al. 2024

Preprint

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Understanding the mechanisms of T-cell antigen recognition that underpin adaptive immune responses is critical for the development of vaccines, immunotherapies, and treatments against autoimmune diseases. Despite extensive research efforts, the accurate identification of T cell receptor (TCR)-antigen binding pairs remains a significant challenge due to the vast diversity and cross-reactivity of TCRs. Here, we propose a deep-learning framework termed Epitope-anchored Contrastive Transfer Learning (EPACT) tailored to paired human CD8+TCRs from single-cell sequencing data. Harnessing the pre-trained representations and the contrastive co-embedding space, EPACT demonstrates state-of-the-art model generalizability in predicting TCR binding specificity for unseen epitopes and distinct TCR repertoires, offering potential values for practical outcomes in real-world scenarios. The contrastive learning paradigm achieves highly precise predictions for immunodominant epitopes and facilitates interpretable analysis of epitope-specific T cells. The TCR binding strength predicted by EPACT aligns well with the surge in spike-specific immune responses targeting SARS-CoV-2 epitopes after vaccination. We further fine-tune EPACT on TCR-epitope structural data to decipher the residue-level interactions involved in T-cell antigen recognition. EPACT not only exhibits superior capabilities in quantifying inter-chain distance matrices and identifying contact residue pairs but also corroborates the presence of molecular mimicry across multiple tumor-associated antigens. Together, EPACT can serve as a useful AI approach with significant potential in practical applications and contribute toward the development of TCR-based diagnostics and immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epitope-anchored contrastive transfer learning for paired CD8⁺T cell receptor-antigen recognition

Zhang,

Wang,

Jiang

et al. 2024

Preprint

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“…Tumor antigens are widely used because they can induce a specific immune response and effectively activate T cells. Tumor cells contain diverse antigens needed for immune activation and are ideal immune stimulators . Compared with tumor cells, tumor cell lysate has more abundant biomarkers, including cell membrane antigens, nucleic acids, cytoplasmic proteins, and polysaccharides .…”

Section: Introductionmentioning

confidence: 99%

“…Tumor cells contain diverse antigens needed for immune activation and are ideal immune stimulators. 18 Compared with tumor cells, tumor cell lysate has more abundant biomarkers, including cell membrane antigens, nucleic acids, cytoplasmic proteins, and polysaccharides. 19 Tumor cell lysate also has several advantages, including a short preparation time, being easy to obtain, and cost-effectiveness, all of which highlight its potential for cancer immune therapy.…”

Section: ■ Introductionmentioning

confidence: 99%

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Huang,

Wang,

et al. 2023

Mol. Pharmaceutics

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Messenger ribonucleic acid (mRNA)-based gene therapy has great potential for cancer gene therapy. However, the effectiveness of mRNA in cancer therapy needs to be further improved, and the delivery efficiency and instability of mRNA limit the application of mRNA-based products. Both the delivery efficiency can be elevated by cell-penetrating peptide modification, and the immune response can be enhanced by tumor cell lysate stimulation, representing an advantageous strategy to expand the effectiveness of mRNA gene therapy. Therefore, it is vital to exploit a vector that can deliver high-efficiency mRNA with codelivery of tumor cell lysate to induce specific immune responses. We previously reported that DMP cationic nanoparticles, formed by the self-assembly of DOTAP and mPEG-PCL, can deliver different types of nucleic acids. DMP has been successfully applied in gene therapy research for various tumor types. Here, we encapsulated tumor cell lysates with DMP nanoparticles and then modified them with a fused cell-penetrating peptide (TAT-iRGD) to form an MLSV system. The MLSV system was loaded with encoded Bim mRNA, forming the MLSV/Bim complex. The average size of the synthesized MLSV was 191.4 nm, with a potential of 47.8 mV. The MLSV/mRNA complex promotes mRNA absorption through caveolin-mediated endocytosis, with a transfection rate of up to 68.6% in B16 cells. The MLSV system could also induce the maturation and activation of dendritic cells, obviously promoting the expression of CD80, CD86, and MHC-II both in vitro and in vivo. By loading the encoding Bim mRNA, the MLSV/Bim complex can inhibit cell proliferation and tumor growth, with inhibition rates of up to 87.3% in vitro. Similarly, the MLSV/Bim complex can inhibit tumor growth in vivo, with inhibition rates of up to 78.7% in the B16 subcutaneous tumor model and 63.3% in the B16 pulmonary metastatic tumor model. Our results suggest that the MLSV system is an advanced candidate for mRNA-based immunogene therapy.

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Oligonucleotide library screening for identification of virus‐specific T‐cell receptors

Welters,

Stadler,

Anastasopoulou

et al. 2024

Eur J Immunol

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Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy

Cited by 35 publications

References 73 publications

Epitope-anchored contrastive transfer learning for paired CD8⁺T cell receptor-antigen recognition

Epitope-anchored contrastive transfer learning for paired CD8⁺T cell receptor-antigen recognition

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Oligonucleotide library screening for identification of virus‐specific T‐cell receptors

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Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy

Cited by 35 publications

References 73 publications

Epitope-anchored contrastive transfer learning for paired CD8+T cell receptor-antigen recognition

Epitope-anchored contrastive transfer learning for paired CD8+T cell receptor-antigen recognition

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Oligonucleotide library screening for identification of virus‐specific T‐cell receptors

Contact Info

Product

Resources

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Epitope-anchored contrastive transfer learning for paired CD8⁺T cell receptor-antigen recognition

Epitope-anchored contrastive transfer learning for paired CD8⁺T cell receptor-antigen recognition