RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma

Abstract

The diversity of T-cell receptor (TCR) repertoires, as generated by somatic DNA rearrangements, is central to immune system function. High-throughput sequencing technologies now allow examination of antigen receptor repertoires at single-nucleotide and, more recently, single-cell resolution. The TCR repertoire can be altered in the context of infections, malignancies or immunological disorders. Here we examined the diversity of TCR clonality and its association with pathogenesis and prognosis in adult T-cell leukemia/lymphoma (ATL), a malignancy caused by infection with human T-cell leukemia virus type-1 (HTLV-1). We analyzed 62 sets of high-throughput RNA sequencing data from 59 samples of HTLV-1−infected individuals—asymptomatic carriers (ACs), smoldering, chronic, acute and lymphoma ATL subtypes—and three uninfected controls to evaluate TCR distribution. Based on these TCR profiles, CD4-positive cells and ACs showed polyclonal patterns, whereas ATL patients showed oligo- or monoclonal patterns (with 446 average clonotypes across samples). Expression of TCRα and TCRβ genes in the dominant clone differed among the samples. ACs, CD4 - positive samples and smoldering patients showed significantly higher TCR diversity compared with chronic, acute and lymphoma subtypes. CDR3 sequence length distribution, amino acid conservation and gene usage variability for ATL patients resembled those of peripheral blood cells from ACs and healthy donors. Thus, determining monoclonal architecture and clonal diversity by RNA sequencing might be useful for prognostic purposes and for personalizing ATL diagnosis and assessment of treatments.

Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis

“…In addition, longitudinal analysis of TCR repertoires demonstrated a correlation of the TCR clonal expansion with HTLV-1 proviral load. ATLL patients also showed monoclonal TCRs compared with ACs, and clonality data observed based on TCR repertoires were completely consistent with clonality analysis based on provirus integration sites (Rowan et al 2016;Farmanbar et al 2019). Recently, Tax 301-309 -specific CTL in HLA-A*2402 ATLL patients and ACs shared highly restricted TCR repertoires by the single-cell analysis (Ishikawa et al 2017).…”

Toward Systems Biomarkers of Response to Immune Checkpoint Blockers

“…Other emerging predictive biomarkers such as tumor mutational burden (TMB) ( 9 , 10 ), signatures of a T cell inflamed tumor microenvironment (TME) either alone ( 10 ) or in combination ( 11 ), and neoantigen load ( 12 – 14 ) are still undergoing clinical trials. In addition, T cell receptor (TCR) diversity has been used as a biomarker to monitor the clonal expansion of T cells in breast cancer, glioma, cervical cancer, and leukemia/lymphoma ( 15 – 18 ). Further efforts both to exploit the utility of these biomarkers and to search for additional ones are still ongoing.…”

Biomarkers and Preclinical Models for Adult T-Cell Leukemia-Lymphoma Treatment

“…Alternatively, variant allele frequency measurements of specific ATL genetic abnormalities provide an alternative measurement of clonal outgrowth of ATL (Farmanbar et al, 2018). Laydon et al (2014) and Farmanbar et al (2019) also reported quantification of HTLV-1 clonality using TCR diversity analysis. However, we have identified subjects in whom two or more TCR gene rearrangements are present within a population of ATL cells with a single proviral integration site (Rauch et al, 2019).…”