Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: Pitfalls in interpretations of functional relevance

Tricia Cottrell, Jiajia Zhang, Boyang Zhang, Genevieve J. Kaunitz, Poromendro Burman, Hok Yee Chan, Franco Verde, Jody E. Hooper, Hans Hammers, Mohamad E. Allaf, Hongkai Ji, Janis Taube, Kellie N. Smith

Research output: Contribution to journalArticlepeer-review

Abstract

T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and-uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.

Original languageEnglish (US)
Article numbere002642
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number7
DOIs
StatePublished - Jul 6 2021
Externally publishedYes

Keywords

  • biostatistics
  • immunologic
  • immunologic techniques
  • immunotherapy
  • receptors
  • t-lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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