Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and “True entropy.” Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8⁺ effector memory and CD4⁺ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.

KEYWORDS:

• Pancreatic cancer
• T-cell receptor repertoire
• cancer immunology
• tumor microenvironment
• immunotherapy
• biomarkers

Disclosure statement

N.B. is a consultant for Santa Ana Bio and Omniscope. No potential conflicts of interest were reported by the other authors.

Author contributions

RF, DD, GH, and VP conceptualized and designed the study. RF, DD, GH, VP, and NB developed the methodology. GH, VP, LC, AJ, GW, JM and YDS acquired data. RF, DD, GH, VP, GW, and NB analyzed and interpreted data. GH, VP, LC, AJ, GW, and JM provided administrative, technical, or material support. RF, DD, GH, VP, LC, AJ, GW, YDS, JM, and VP wrote, reviewed, and/or revised the manuscript. RF and DD supervised the study. Order of co-first authorship was determined by coin-toss.

Data availability statement

All software packages in this study are publicly available. All code used to generate figures is available at this location (https://github.com/WashU-TCR-PDAC), and de-identified patient data can be made available upon request. TCRb CDR3 sequences will be made publicly available on Adaptive Technologies Immunoseq Analyzer Portal.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2024.2320411.

Additional information

Funding

The work was supported by the National Institutes of Health [P30CA091842, F30CA254087], Washington University School of Medicine Dean’s Fellowship, The David Riebel Cancer Research Fund, Washington University SPORE in Pancreas Cancer [P50CA196510-05], The DeNardo Scholar Fellowship, Washington University School of Medicine Dean’s Medical Student Research Fellowship for the MPHS Yearlong Research Program. This work was also supported by Adaptive Biotechnologies.