Distinct outcomes with the detection of endemic Burkitt lymphoma, T-cell receptor (TCR) complementarity determining region-3s (CDR3s) matching known anti-HIV TCR CDR3s.

Abstract

7067 Background: The adaptive immune response is represented by diverse complementary determining region 3’s (CDR3s), which frequently represent antigen contact points and can be obtained from sequencing data. In particular, T-cell receptor (TCR) CDR3s in tumors have added an additional dimension to investigating the role of viruses in tumor development. Further, identifying TCR V- and J-gene segment usage, HLA allele combinations has been shown to represent outcome distinctions in various cancers. Given that endemic Burkitt lymphoma (BL) is well-known to be caused by Epstein-Barr virus (EBV), we aimed to characterize endemic BL adaptive immune features using TCR recombination reads, focusing on anti-HIV CDR3s and the presence of specific TCR V/J, HLA allele combinations. Methods: The Cancer Genome Characterization Initiative – Burkitt Lymphoma Genome Sequencing Project provided data available at the Genomic Data Commons website: 160 RNA-seq files from primary tumor that represented 105 cases. Phenotypic data representing these cases included gender, race, age at diagnosis, days to last follow-up, vital status, and Ann Arbor pathologic stage. The RNA-seq files were mined for TCR recombination reads using a high-stringency search algorithm (Chobrutskiy et al. 2020) and for HLA alleles utilizing xHLA (Xie et al. 2017). Anti-HIV CDR3s and specific TCR V/J, HLA allele combinations were then correlated with the progression of endemic BL as measured by overall survival (OS) and staging. Results: 47,302 productive TCR CDR3 recombination reads were recovered across all samples. We identified that the 22 cases with anti-HIV TRA CDR3s had improved OS as compared to those without an anti-HIV TRA recovery (median OS not reached vs. 215 days; log-rank p = 0.0013). Similarly, the 74 cases with anti-EBV TRA CDR3s were associated with an improved OS as compared to remaining cases (median OS 437 vs. 164 days; log-rank p = 0.005). Decreased disease progression as measured by lower pathologic stage was also noted in patients with anti-HIV TRA and TRB s compared to remaining cases (Mann-Whitney U p-value: 0.05, 0.01 respectively). Lastly, we identified five TCR V/J, HLA allele combinations which were associated with survival where the individual V or J gene segment and HLA allele was not associated with survival. An example of this were 33 cases with TRAV12-3 and DQB1*05:01, whose OS did not reach the median compared to the 199-day median OS of all other cases (log-rank p = 0.01). Conclusions: Early control of tumor progression via the T-cell response, whether by increased anti-viral T-cell receptors or via effective combination of antigen presentation and TCR antigen binding, appears to impact the progression of BL. Specifically, the success of anti-HIV TCRs indicates that treating co-infection with HIV may be a key factor in slowing disease progression.