Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans.

Miri Gordin,Moriah Gidoni,Irun R Cohen,Francois Vigneault,Hagit Philip,Gur Yaari,Alona Zilberberg,Christopher Clouser,Kristofor Adams,Sol Efroni,Raanan Margalit,Benny Chain

doi:10.1371/journal.pcbi.1008486

Abstract

The partial success of tumor immunotherapy induced by checkpoint blockade, which is not antigen-specific, suggests that the immune system of some patients contain antigen receptors able to specifically identify tumor cells. Here we focused on T-cell receptor (TCR) repertoires associated with spontaneous breast cancer. We studied the alpha and beta chain CDR3 domains of TCR repertoires of CD4 T cells using deep sequencing of cell populations in mice and applied the results to published TCR sequence data obtained from human patients. We screened peripheral blood T cells obtained monthly from individual mice spontaneously developing breast tumors by 5 months. We then looked at identical TCR sequences in published human studies; we used TCGA data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects. We now report that mice spontaneously developing breast cancer manifest shared, Public CDR3 regions in both their alpha and beta and that a significant number of women with early breast cancer manifest identical CDR3 sequences. These findings suggest that the development of breast cancer is associated, across species, with biomarker, exclusive TCR repertoires.

Highlights

The CDR3 region of the T-cell receptor (TCR) binds the peptide epitopes presented by MHC molecules to antigenspecific T cells; the CDR3 region directs T-cell antigen specificity [1]
We looked at identical TCR sequences in published human studies; we used The Cancer Genome Atlas (TCGA) data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects
Since mice and humans have been found to share prevalent Public TCR sequences, we carried out this study in two stages: In the first stage we carried out a longitudinal study of TCR repertoires in mice undergoing the development of spontaneous, transgene-engineered breast cancer; the results uncovered multiple CDR3 regions sequences that were Public and Exclusive to mice developing tumors; these sequences were undetectable in mice lacking the breast-cancer transgene

Summary

Introduction

The CDR3 region of the TCR binds the peptide epitopes presented by MHC molecules to antigenspecific T cells; the CDR3 region directs T-cell antigen specificity [1]. Despite the astronomical numbers of possible CDR3 nucleotide (NT) recombinations [2], more than 10^18 different TCR sequences, healthy mice and humans manifest shared, Public TCR CDR3 amino acid (AA) sequences that seem to be enriched for associations with self-reactivity, allo-reactivity and tumors [3,4]. These Public TCR repertoires seem to emerge as a consequence of selection and are rich in convergent recombination–different (NT) recombinations encode identical (AA) CDR3 sequences. We developed a metric to learn whether women with breast cancer manifested specific TCR sequences present in mice developing breast cancer

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