Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the most effective strategy for high risk patients with acute myeloid leukemia (AML). Leukemia specific neoantigens when presented by the major histocompatibility complexes (MHCs) are recognized by the T cell receptors (TCR) triggering the graft versus leukemia effect. Unique TCR signature is generated by a complex rearrangement process of an array of variable (V), diversity (D), and joining (J) exons to form a functional receptor with complementary determining regions 3 responsible for the interaction between the TCR and the peptide-MHC. The generated TCR repertoire undergoes dynamic changes with the onset and progression of leukemia and with the course of treatment.
To better understand how the TCR repertoire impacts disease progression and patient’s clinical outcome, we leveraged RNA-seq data from The Cancer Genome Atlas (TCGA) to extract the TCR sequences using TRUST4 and MIXCR and examined the association between features of the TCR repertoire in patients with AML and their clinical and molecular characteristics. Data were analyzed by normalizing the number of unique clones to the number of total RNA-seq reads specific for each sample and one minus peripheral blood blast percentage.
Both TRUST4 and MIXCR data showed a strong correlation between the number of unique clones for TCRA and TCRB per patient (r=0.944, p <0.001 for TRUST4, r=0.941, p <0.001 for MIXCR). Only 1389 TCRA clones (28.9%; TRUST4: 3450, MIXCR: 2747) and 1327 TCRB (31.3%; TRUST4: 3986, MIXCR: 1584) unique clonotypes were shared by the two computational tools. Nevertheless, we were able to identify the majority of the known TRAV and TRBV segments. Our analysis shows that the normalized number of unique TCRA and TCRB clones were lower in patients carrying FLT3 mutations (TRUST4: TCRA: p=0.013; TCRB: p=0.058; MIXCR: TCRA: p=0.043; TCRB: p=0.030), and higher in patients carrying IDH1 mutations (TRUST4: TCRA: p=0.037; TCRB: p=0.038; MIXCR: TCRA: p=0.037; TCRB: p=0.002) compared with patients carrying the wild type gene. No significant difference was observed for DNMT3A, NPM1, TET2, RUNX1, CEBPA IDH2, NRAS, WT1 and TP53 compared with wild type. Although the normalized number of unique TCR clones was not significantly associated with patient’s overall survival, we found that patients that shared more than five TCRB clones with other patients had an improved overall survival compared with patients that shared less than 5 clones (median OS: 55.4 vs 17 months, p=0.058).
Despite the limitations of low TCR gene coverage associated with RNAseq data and the small sample size, we were able to find associations between TCR repertoire and clinical and molecular features in patients with AML using two different computational tools. This study further supports the need for TCR-Seq analyses to provide the depth needed to characterize the TCR repertoire in patients with AML.
Citation Format: Mateusz Pospiech, Mukund Tamizharasan, Yu-Chun Wei, Advaith M. Kumar, Mimi Lou, Joshua Milstein, Houda Alachkar. Features of the TCR repertoire associate with patient’s clinical and molecular characteristics in acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6547.