Abstract
While the role of anti-cytomegalovirus (CMV) T-cell responses in the cancer setting is becoming increasingly recognized, the association between CMV and survival outcomes has not been subject to study through more recent immunogenomic approaches. This study aimed to investigate the association between anti-CMV T-cell receptor (TCR) sequences and improved survival outcomes in two types of cancers where the role of CMV remains currently underexplored, stomach adenocarcinoma (STAD) and soft tissue sarcoma (SARC). The significance of this study is that, to our knowledge, it is the first to identify a potential prognostic role of CMV in both STAD and SARC and highlights the potential for future development of anti-CMV T-cell therapies.
We extracted TCR recombination reads from whole exome sequencing (WXS) and RNA sequencing (RNASeq) files of STAD and SARC samples from the Cancer Genome Atlas (TCGA) and matched the corresponding TCR complementarity determining region-3 (CDR3) AA sequences represented by these reads to known anti-CMV CDR3 sequences.
Results indicated that, in STAD cases, the recovery of both TRA and TRB recombination reads from WXS files, from either normal blood or tumor samples, which corresponded to AA sequences matching anti-CMV CDR3s, correlated with improved disease-free survival (DFS) (logrank p=0.025) and improved overall (p=0.026), progression-free (p=0.015), and disease specific (p=0.026) survival on an STP comparison (i.e., a comparison at 45 months). Within the SARC WXS dataset, these were associated with better overall survival (OS) (logrank p=0.021) and disease-specific survival (DSS) (logrank p=0.008). However, TCR CDR3s represented by recombination reads recovered from RNAseq files and matching anti-CMV TCR CDR3 AA sequences correlated with lower DFS probabilities (i.e., STAD STP comparison at 45 months, p=0.035, SARC STP comparison at 65 months, p=0.032).
This study reveals a novel association between anti-CMV TCR sequences and survival probability in STAD and SARC. This suggests that TCR CDR3s may be possible indicator of prognosis for STAD and SARC and supports further research into anti-CMV CDR3s as a tool for the development of immunotherapy for these cancers. Additionally, the contrasting results between WXS and RNASeq-derived sequences warrant further investigation into the timing and nature of anti-CMV immune responses in cancer progression. One explanation for these results include the possibility that exposure to CMV prior to onset or progression of cancer may lead to better survival probability, while a potentially active T-cell response to CMV during cancer onset or progression could represent an ongoing comorbidity.
Utsav Kapoor, Michael T. Aboujaoude, Konrad Cios, Andrea Chobrutskiy, Boris I. Chobrutskiy, George Blanck. Detection of anti-CMV TCR CDR3s correlates with increased survival for soft tissue sarcoma and stomach adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6254.
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