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Deep learning-based prediction of the T cell receptor–antigen binding specificity


Neoantigens play a key role in the recognition of tumour cells by T cells; however, only a small proportion of neoantigens truly elicit T-cell responses, and few clues exist as to which neoantigens are recognized by which T-cell receptors (TCRs). We built a transfer learning-based model named the pMHC–TCR binding prediction network (pMTnet) to predict TCR binding specificities of the neoantigens—and T cell antigens in general—presented by class I major histocompatibility complexes. pMTnet was comprehensively validated by a series of analyses and exhibited great advances over previous works. By applying pMTnet to human tumour genomics data, we discovered that neoantigens were generally more immunogenic than self-antigens, but human endogenous retrovirus E (a special type of self-antigen that is reactivated in kidney cancer) is more immunogenic than neoantigens. We further discovered that patients with more clonally expanded T cells that exhibit better affinity against truncal rather than subclonal neoantigens had more favourable prognosis and treatment response to immunotherapy in melanoma and lung cancer but not in kidney cancer. Predicting TCR–neoantigen/antigen pairing is one of the most daunting challenges in modern immunology; however, we achieved an accurate prediction of the pairing using only the TCR sequence (CDR3β), antigen sequence and class I major histocompatibility complex allele, and our work revealed unique insights into the interactions between TCRs and major histocompatibility complexes in human tumours, using pMTnet as a discovery tool.

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Fig. 1: Deep learning the TCR binding specificity of neoantigens.
Fig. 2: Validation of pMTnet.
Fig. 3: Prospective validation of pMTnet predictions.
Fig. 4: Structural analyses support the predicted TCR–pMHC interactions.
Fig. 5: Characterizing the TCR–pMHC interactions in human tumours.
Fig. 6: Efficiencies of TCR–neoantigen interactions impact tumour progression.

Data availability

Details on data used for the training and validation of pMTnet, including sample size and role in the machine learning process, are presented in the Supplementary Information. The training and testing datasets are shared on our github repository: The processed TCR-seq and scRNA-seq data generated from the in-house patient donor are also archived at The raw scRNA-seq plus TCR-seq data have been archived on NIH GEO with the accession number GSE173165.

For the NIES analyses, the public patient sequencing datasets are from TCGA, Liu et al.43, Van Allen et al.44 and Hugo et al.45. The raw RNA-seq and exome-seq data of the in-house IL2 cohort patients can be downloaded from the European Genome Phenome Archive with accession number EGAS00001003605 through controlled access. Source data are provided with this paper.

Code availability

The pMTnet software is available on GitHub at (ref. 55). Pipeline for HERV expression detection is available on GitHub at (ref. 56). QBRC mutation calling pipeline is available on GitHub at (ref. 57). QBRC neoantigen calling pipeline is available on GitHub at (ref. 58).


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The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/01/19. We acknowledge D. Liu, B. Li and J. Ostmeyer from UT Southwestern for their helpful advice on our project. We acknowledge the authors of the phs000452.v3.p153 and phs001493.v1.p154 datasets, as well as the funding agencies that supported these studies and dbGaP that supported the archiving of these datasets. This study was supported by the National Institutes of Health (NIH) (grant nos. CCSG 5P30CA142543/TW and R01CA258584/TW), Cancer Prevention Research Institute of Texas (grant no. CPRIT RP190208/TW), University of Texas MD Anderson Cancer Center (Lung Cancer Moon Shot/AR), the University Cancer Foundation at the University of Texas MD Anderson Cancer Center (Institutional Research Grant/AR), the Waun Ki Hong Lung Cancer Research Fund (A.R.), Exon 20 Group (A.R.) and Rexanna’s Foundation for Fighting Lung Cancer (A.R.).

Author information

Authors and Affiliations



T.L. created the TCR/pMHC pairing prediction model and carried out the primary data analyses. Z.Z. created the TCR embedding algorithm. J.Z. carried out structural analyses. P.J., C.B., J.V.H., D.L.G. and A.R. contributed the in-house validation data. A.R., Y.W., X.X., J.W. and L.X. provided input on the study design and reviewed the manuscript. T.W. supervised the whole study.

Corresponding authors

Correspondence to Alexandre Reuben or Tao Wang.

Ethics declarations

Competing interests

We are applying for formal intellectual property protection on the pMTnet model and software. A.R. serves on the Scientific Advisory Board and has received honoraria from Adaptive Biotechnologies.

Additional information

Peer review information Nature Machine Intelligence thanks Alok Joglekar, Peng Jiang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 More examples showing the successful embedding of TCRs by the auto-encoder.

(a) Heatmaps of the original TCR CDR3β sequences, embedded by the ‘Atchley factors’ and all padded with zeros to the length of 80 amino acids. (b) Heatmaps of the re-constructed TCR CDR3β sequences for the same TCRs. (c) Scatterplots showing the consistency between ‘Atchley factor’ values of the original and re-constructed TCRs. Blue points represent tiles in the heatmaps in (a) and (b). The red dashed lines are for y = x.

Source data

Extended Data Fig. 2 Differential analysis of the expression levels of HERVs between tumor samples and normal samples in different RCC cancer types and data cohorts.

In addition to EU137846.2 (the known HERV-E), the HERVs whose tumor-over-normal expression ratio is >3 in any of the type/cohort, and whose normal tissue expression is <3 are also shown. There are five such HERVs.

Source data

Extended Data Fig. 3 Efficiencies of TCR-neoantigen interactions impact response to immunotherapies.

(a) Association between NIES and overall survival of melanoma patients on immunotherapies. The patients were split by the median of NIES in each cohort and then combined. The P-value for the log-rank test is shown. (b) Association between NIES and the response of metastatic gastric cancer patients. The overall survival or progression-free survival data are not made available from the original publication, so we used the RECIST response variables. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). There are 40 gastric cancer patients. An ordinal Jonckheere test is employed to investigate whether patients with better response to immunotherapies also have higher NIES scores. In this test, all categories are compared together to investigate whether an overall trend exists across all categories. (c) Boxplots of bootstrap P values evaluating the robustness of comparison between NIES, neoantigen load, T cell infiltration level, and TCR diversity. One P-value is generated from one bootstrap resample of each cohort, and the two-sided Wilcoxon signed-rank test was carried out for the bootstrap P values to assess whether differences are significant between different biomarkers. NS: P>0.01, *: P = 0.01–0.05, **: P = 0.001–0.01, ***: P = 0.0001–0.001, ****:P < 0.0001. For boxplots in (b) and (c), box boundaries represent interquartile ranges, whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range, and the line in the middle of the box represents the median.

Source data

Extended Data Fig. 4

Association of NIES with treatment response of (a) melanoma, (b) metastatic gastric cancer, and (c) kidney cancer patients on checkpoint-inhibitor treatment. There are 33 kidney cancer patients from the Miao cohort. The same analyses as in Extended Data Fig. 3 were carried out, except that the binding affinity cutoffs for assigning TCRs to neoantigens were varied at several possible values.

Source data

Extended Data Fig. 5

Association of neoantigen load, T cell infiltration level, and TCR repertoire diversity with treatment response of (a) melanoma, (b) metastatic gastric cancer, and (c) kidney cancer patients on checkpoint-inhibitor treatment. The same analyses as in Extended Data Fig. 3 were carried out for these biomarkers.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–13 and Supplementary Tables 1–5.

Reporting Summary

Source data

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Statistical source data for Fig. 2

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Source Data Extended Data Fig. 1

Statistical source data for Extended Data Fig. 1

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Statistical source data for Extended Data Fig. 2

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Statistical source data for Extended Data Fig. 3

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Statistical source data for Extended Data Fig. 4

Source Data Extended Data Fig. 5

Statistical source data for Extended Data Fig. 5

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Lu, T., Zhang, Z., Zhu, J. et al. Deep learning-based prediction of the T cell receptor–antigen binding specificity. Nat Mach Intell 3, 864–875 (2021).

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