Analysis of T cell receptor clonotypes in tumor microenvironment identifies shared cancer-type-specific signatures

Abstract

Despite the conventional view that a truly random V(D)J recombination process should generate a highly diverse immune repertoire, emerging reports suggest that there is a certain bias toward the generation of shared/public immune receptor chains. These studies were performed in viral diseases where public T cell receptors (TCR) appear to confer better protective responses. Selective pressures generating common TCR clonotypes are currently not well understood, but it is believed that they confer a growth advantage. As very little is known about public TCR clonotypes in cancer, here we set out to determine the extent of shared TCR clonotypes in the intra-tumor microenvironments of virus- and non-virus-driven head and neck cancers using TCR sequencing. We report that tumor-infiltrating T cell clonotypes were indeed shared across individuals with the same cancer type, where the majority of shared sequences were specific to the cancer type (i.e., viral versus non-viral). These shared clonotypes were not particularly enriched in EBV-associated nasopharynx cancer but, in both cancers, exhibited distinct characteristics, namely shorter CDR3 lengths, restricted V- and J-gene usages, and also demonstrated convergent V(D)J recombination. Many of these shared TCRs were expressed in patients with a shared HLA background. Pattern recognition of CDR3 amino acid sequences revealed strong convergence to specific pattern motifs, and these motifs were uniquely found to each cancer type. This suggests that they may be enriched for specificity to common antigens found in the tumor microenvironment of different cancers. The identification of shared TCRs in infiltrating tumor T cells not only adds to our understanding of the tumor-adaptive immune recognition but could also serve as disease-specific biomarkers and guide the development of future immunotherapies. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-021-03047-7.

Features of the TCR repertoire associate with patients' clinical and molecular characteristics in acute myeloid leukemia

“…Public TCRs were previously described in infectious diseases, cancer and autoimmune disease and were found to associate with clinical outcome (62)(63)(64)(65)(66)(67). Consistently with previous studies we found that public CDR3s have shorter amino acid length (68).…”

Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19

“…As expected, the transcriptomic status of the cells (i.e., distribution of the cells on UMAP) within and across the clonotypes were heterogenous, suggesting that the fate of CTLs such as cell division, differentiation, survival or cell death should have been regulated by various factors including basal state of the cells, amount and frequency of the antigen stimulation or co-stimulation, cytokines etc., during T cell activation in the clinical course of disease. Recent advanced platforms are accumulating information on public TCRs in infectious diseases and cancers 60 – 62 . In HIV-infected patients, there are rare subjects who could control viral propagation without therapy, called HIV controllers 61 .…”