Immune DNA signature of T-cell infiltration in breast tumor exomes.

Eric Levy,Olivier Harismendy,Michelle Dow,Brian Woo,Rachel Marty,Valentina Gárate Calderón,Ricardo Armisen,Hannah Carter

doi:10.1038/srep30064

Abstract

Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. The Cancer Genome Atlas (TCGA) represents the largest collection of cancer molecular data, but lacks detailed information about the immune environment. Here, we show that exome reads mapping to the complementarity-determining-region 3 (CDR3) of mature T-cell receptor beta (TCRB) can be used as an immune DNA (iDNA) signature. Specifically, we propose a method to identify CDR3 reads in a breast tumor exome and validate it using deep TCRB sequencing. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. Only 2/839 TCRB clonotypes were shared between patients and none associated with a specific HLA allele or somatic driver mutations. The iDNA biomarker enriches the comprehensive dataset collected through TCGA, revealing associations with other molecular features and clinical outcomes.

Highlights

Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types
In order to further distinguish the different cell type populations, other studies have used immunohistochemistry to detect cell surface markers (e.g. CD3, CD8, CD20), demonstrating, for example, that the predictive value of B-cell infiltration is independent of cancer subtype or other clinical factors[8], or that CD8+T-cell infiltration is of good prognosis in basal TNBC5
We sequenced the repertoire of three triple negative breast cancer (TNBC) samples selected for their variable tumor infiltrating lymphocytes (TILs) contents

Summary

Introduction

Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. The technical validity and clinical utility of TCR repertoire characterization in tumors remains to be established It is not yet clear whether the quantity (fraction of T-cells) or the diversity (relative abundance of specific clones) is more important to predict disease progression and response to treatment. We identify CDR3 reads in TCGA breast cancer tumors, and show their correlation with other markers of immune infiltration We further evaluate their prognostic value in breast cancer subtype and investigate clonotype diversity and sharing between patients and specimens

Methods

Results

Conclusion