Research ArticleArticles
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Worse Wilms’ Tumor Outcomes Associated With Chemical Complementarity for Multiple T-Cell Receptor CDR3-CMV Epitope Pairs

KASEY L. RIGBY, MICHAEL J. DIAZ, ETIENNE C. GOZLAN, DOROTTYA B. KACSOH, JOANNA J. SONG, TABITHA R. HUDOCK, ANDREA CHOBRUTSKIY, BORIS I. CHOBRUTSKIY and GEORGE BLANCK
Cancer Genomics & Proteomics September 2024, 21 (5) 439-447; DOI: https://doi.org/10.21873/cgp.20462

Abstract

Background/Aim: Wilms’ tumors are pediatric renal tumors that generally have a good prognosis and outcomes. Viral illnesses have been linked to development of neoplasms and should be considered as a factor that could modulate overall survival. Materials and Methods: We considered recently developed adaptive immune receptor, genomics and bioinformatics approaches to assess the potential impact of cytomegalovirus (CMV) infections in Wilms’ tumor. Results: T-cell receptor (TCR) complementarity determining region-3 (CDR3) amino acid sequences from Wilms’ tumor specimens represented by the Therapeutically Applicable Research to Generate Effective Treatments dataset were compared with known anti-CMV TCR CDR3s, indicating that cases representing the anti-CMV TCR CDR3s had worse outcomes. Then, a chemical complementarity scoring approach for the Wilms’ tumor, TCR CDR3s and a series of CMV antigens further indicated that cases representing a higher chemical complementarity to the CMV antigens had worse outcomes. Conclusion: Overall, we present a potentially novel method to assess CMV infections and identify patients who could benefit from therapies that address such infections.

Key Words:

Wilms’ tumor, also known as nephroblastoma, is a malignancy of the kidney that is most often seen in pediatric patients. Wilms’ tumor is comprised of malignant renal tubules and glomeruli tissue, and it was first described in 1899 by Dr. Max Wilms (1). Wilms’ tumor is the most common childhood renal tumor, as reported by the National Childhood Cancer Registry, with renal tumors overall comprising an estimated 5% of tumors in children aged 0-4 years (2).

The current treatment of unilateral Wilms’ Tumor consists of nephrectomy for histological staging and tumor removal followed by chemotherapy, if necessary (3). Patients with more extensive disease, such as metastatic disease, bilateral involvement of the kidneys, or those with initially inoperable tumors are generally treated with chemotherapy before surgery to potentially increase successful resection and/or removal of the neoplasm (4). The long-term survival of a patient who is presumably or apparently treated successfully is 90% (5). Despite these successes, there is a remaining subset of patients that do not respond to treatment. This may be due to variation in patients’ long-term experiences and exposures, including the occurrence of viral infections (6).

There are well-documented examples of infections being linked to the development of cancers. In addition, cancer treatments can affect the ability of the body to respond to an infection (7). In both instances, infection can lead to a more severe disease presentation in a patient, which can lead to overall decreased survival. For example, human papillomavirus and Epstein-Barr virus are directly causative for cancer development (8, 9). Cytomegalovirus (CMV) infection is a common viral infection that can present asymptomatically and has been linked to glioblastoma multiforme with the degree of infection, based on the percentage of cells expressing CMV protein(s), having been linked to altered survival rates in the disease process (10, 11). At the time of writing, there have been a total of eleven infectious diseases that have been classified as carcinogenic to humans, with an incidence analysis attributing about 2.2 millions of worldwide cancer cases to the carcinogenic effect of these infectious diseases (12, 13).

T-lymphocytes are the main component of the adaptive immune system detecting and responding to viral infections (14). T-lymphocytes express T-cell receptors (TCRs) that target viral epitopes associated with an infection, with the TCR complementarity determining region-3 (CDR3) amino acids (AAs) being a highly likely interaction point with viral epitopes. Therefore, the CDR3s of the TCR α-chains and β-chains, hereafter referred to as TRA and TRB, respectively, have the potential to inform about past or current infections. TCR CDR3s directed against viral epitopes have been identified and well-documented (15). Thus, CDR3s representing exact matches to anti-viral, CDR3 AA sequences are very likely consistent with evidence of a past or current infection. The objective of this study was to determine whether there was a difference in the outcomes of Wilms’ tumor cases that have evidence of CMV exposure, via the detection of anti-CMV TCR CDR3s.

Materials and Methods

Extraction of the TRA and TRB recombination reads from the Wilms’ tumor RNAseq files. The TRA and TRB recombination reads were extracted from the Wilms’ tumor RNAseq files represented by the Therapeutically Applicable Research to Generate Effective Treatment (TARGET, phs000218) program, managed by the Office of Cancer Genomics and the Cancer Therapy Evaluation Program of the National Cancer Institute (Bethesda, MD, USA). The RNAseq files were downloaded to the University of South Florida research computing clusters, via database of genotypes and phenotypes (dbGaP) approved protocol number, 16405. The recombination read extraction process has been substantially benchmarked, particularly in (16). The latest version of the software is freely available at https://github.com/kcios/2021. Software development and design can be obtained from (17-19). The processing provides for translation of the CDR3 AA sequences for the productive recombinations. Data representing the TRA and TRB recombination reads are in Table S1 of the supporting online material (SOM).

Epitopes sourced from the Immune epitope database (IEDB) (20). Epitopes identified as T-cell epitopes at the IEDB were sourced for analyses as indicated (Results). Specifically, ten such epitopes were evaluated in this report, representing the top ten CMV epitopes with regard to number of literature references as indicated by the IEDB (Table S2).

Anti-CMV, TCR CDR3 matching by matching AA sequences (exactly) of the anti-CMV TCR CDR3s and the WT TCR CDR3s. Anti-CMV CDR3 AA sequences of https://vdjdb.cdr3.net/ (15) were compared to the CDR3 AA sequences from the TARGET Wilms’ tumor, TRA and TRB dataset to identify cases representing exact matches (Results, Table S3).

Assessment of the TCR-CMV epitope chemical complementarity scores (CSs). The chemical complementarity of the Wilms’ tumor CDR3s and CMV antigens/epitopes was obtained via the adaptivematch.com web tool. The processing performed by this web tool is based on a “sliding window” calculation for chemical complementarity for the CDR3 and a candidate epitope or antigen, as described in (21). Briefly, the CDR3 and epitope amino acids (AAs) are aligned, and a value is assigned to positively and negatively charged AAs, as determined by their R-groups, that are directly across from one another. A lesser value is assigned if the positive and negative charges are close but not directly aligned. The two AA sequences are then shifted by one AA and the calculation is repeated. The alignment that produces the highest chemical complementarity score (CS), and the CS, are retained as adaptivematch.com output. The output also includes a CS that is determined by a combination of electrostatic and hydrophobic interactions, termed the Combo CS. These scores are reported (by adaptivematch.com) along with Electrostatic CSs and Hydrophobic (Hydro) CSs. Only the Electrostatic and Combo CSs were used in this report. The web tool also assesses survival and gene expression distinctions for cases that have higher or lower CSs. The survival probability distinctions indicated by the adaptivematch.com output were verified as indicated below. The web tool has been substantially benchmarked in (22, 23). Example adaptivematch.com input and output files are in Tables S4-S13. However, note that the input for adaptivematch.com requires a CSV file. Thus, the input indicated in the SOM tables would need to be transferred to a CSV file for analysis.

Survival analyses. Survival analyses performed by adaptivematch.com were verified using cbioportal.org. Finally, the results were re-verified using R software, and these latter data are provided in the figures of this report (Results) (24, 25).

Patient death reasons. The cause of death in the cases in the Wilms’ tumor TARGET (phs000218) dataset were indicated as “TUMOR”, “TUMOR AND TOXICITY”, “INFECTION”, and “None”, with “None” referring to cases that had not expired during the study. To determine whether the subdivisions of the upper and lower 50th percentile CS groups, for each Kaplan-Meier (KM) plot, with regard to the previously indicated causes of death, also represented significant differences, we analyzed the causes of death using a Chi-squared test of independence.

Multivariate analyses. Multivariate Cox regression analyses were performed using the IBM Statistical Product and Service Solutions investigating the correlation of OS probabilities with diagnosis age, the event type (relapse versus none and progression versus none), the histology classification of diffuse anaplastic Wilms’ tumors (DAWT) versus favorable histology Wilms’ tumors (FHWT), the Neoplasm American Joint Committee on Cancer Clinical Group Stage (Stages I-IV), with Stage I assigned as the reference category, and the lower 50th percentile CS versus upper 50th percentile CS. Cases that were missing one or more of the variables analyzed were excluded from the multivariate analysis.

Ethical approval statement. Access to the TARGET RNAseq files was via dbGaP project approval number 16405.

Results

Initial consideration of TCR anti-CMV CDR3s and survival outcomes. We first determined whether there was an occurrence of anti-CMV CDR3s in Wilms’ tumor-specimen, RNAseq files, based on an exact AA sequence match of the anti-CMV TCR (TRA+TRB) CDR3s, as indicated by the database at https://vdjdb.cdr3.net/ (15), and the Wilms’ tumor TCR CDR3 AA sequences (Table S1). We next assessed the overall survival (OS) probabilities for the cases with the anti-CMV CDR3s, based on this exact match standard, in comparison to cases that had no such anti-CMV CDR3s. A KM analysis did not indicate a significant OS probability distinction between these two Wilms’ tumor case sets, however, a single time point assessment indicated a trend of a worse OS probability for cases with TCR CDR3s that were an exact AA sequence match to the anti-CMV TCR CDR3s AAs (logrank p=0.128; Table S2).

Given the above, preliminary indication of a worse OS probability for cases with anti-CMV CDR3s, we considered the possibility that potential anti-CMV CDR3s could be effectively indicated by chemical complementarity of the Wilms’ tumor TCR CDR3s to CMV antigens. To test this hypothesis, we assessed chemical complementarity scores (CSs) of the TCR CDR3s from the Wilms’ tumor RNAseq files and known TCR CMV antigens, using the adaptivematch.com web tool. The Wilms’ tumor, TRA and TRB CDR3 sets were tested separately. Thus, TRA CDR3s were used to calculate the CSs for several known CMV antigens. Results indicated significant OS probability distinctions for cases representing the upper and lower 50th percentile groups for the UL29 and IE1 CMV antigens, with the lower 50th percentile representing a better OS survival probability (Figure 1). In the case of UL29, the better OS probability for the lower 50th percentile group represented a calculation of the Electrostatic CSs using the entire AA sequence for UL29 as the candidate antigen for adaptivematch.com (Figure 1A; Table S3-S5). In the case of IE1, the better OS probability for the lower 50th percentile group represented a calculation of the Electrostatic CSs using a fragment of the IE1 AA sequence, for this report termed, Fragment 7 (Figure 1B; Table I), a fragment that was generated from an arbitrary division of the original, full-length IE1 AA sequences.

Figure 1.
Figure 1.

Higher electrostatic CSs for TRA CDR3-CMV antigens associated with worse OS probabilities, with log rank p-values indicated in the figure. (A) KM) assessment of upper (black line, arrowhead) and lower (grey line) 50th percentile groups for TRA CDR3-UL29 (full length) Electrostatic CSs; Cox-regression p-value: not significant. (B) KM assessment of upper (black line, arrowhead) and lower (grey line) 50th percentile groups for TRA CDR3-IE1-Fragment 7 Electrostatic CSs; Cox-regression p=0.045. CSs: Complementarity scores; OS: overall survival; KM: Kaplan-Meier.

View this table:
Table I.

CMV antigens representing OS probability distinctions.

The above approach was repeated for TRB CDR3s, i.e., Electrostatic CSs were calculated based on CDR3 AA sequences representing TRB recombination reads recovered from the Wilms’ tumor RNAseq files. Results indicated that the lower 50th percentile Electrostatic CSs indicated a better OS probability for arbitrarily established fragments representing CMV proteins, pp65 and IE2, respectively. The fragments were termed Fragment 6 for pp65 (Figure 2A); and Fragment 5, for IE2 (Figure 2B; See also Table I).

Figure 2.
Figure 2.

Higher electrostatic CSs for TRB CDR3-CMV antigens associated with worse OS probabilities, with log rank p-values indicated in the figure. (A) KM assessment of upper (black line, arrowhead) and lower (grey line) 50th percentile groups for TRB CDR3-pp65-Fragment 6 Electrostatic CSs; Cox-regression p=0.035. (B) KM assessment of upper (black line, arrowhead) and lower (grey line) 50th percentile groups for TRB CDR3-IE2-Fragment 5 Electrostatic CSs; Cox-regression p-value: 0.049. CSs: Complementarity scores; OS: overall survival; KM: Kaplan-Meier.

As noted above, OS probability distinctions for both TRA and TRB-related CSs were obtained for different CMV proteins. Thus, we considered the possibility of sourcing previously defined TCR CMV epitopes and determining the relation between the TRA and TRB CSs, respectively, with OS probabilities. As above (Figure 1 and Figure 2), CSs were calculated based on CDR3 AA sequences representing TRA and TRB recombination reads recovered from the Wilms’ tumor RNAseq files. Results indicated that for TRA CDR3s, the lower 50th percentile Electrostatic CSs indicated a better OS probability for the IE1 protein epitope from the IEDB, termed IEDB-51089 (QIKVRVDMV) (Figure 3A, Table I). For the TRB CDR3s, the lower 50th percentile Combo CSs indicated a better OS probability for the same IE1 protein epitope from the IEDB (Figure 3B, Table I).

Figure 3.
Figure 3.

Higher electrostatic and combo CSs for TRA CDR3-CMV epitopes (IEDB) and TRB CDR3-CMV epitopes (IEDB) associated with worse OS probabilities, with log rank p-values indicated in the figure. (A) KM assessment of upper (black line, arrowhead) and lower (grey line) 50th percentile for TRA CDR3-IE1-IEDB-51089 (QIKVRVDMV) Electrostatic CSs; Cox-regression p=0.067. (B) KM assessment of upper (black line, arrowhead) and lower (grey line) 50th percentile groups for TRB CDR3-IE1- IEDB-51089 (QIKVRVDMV) Combo CSs; Cox-regression p=0.007. CSs: Complementarity scores; KM: Kaplan-Meier.

Patient death-reasons. As noted above, the OS probability distinctions between the upper and lower 50th percentile groups based on the indicated Electrostatic CSs showed significant results. Thus, we next assessed the death-reasons to determine whether there was a death-reason distinction between the above identified, distinct survival groups. Death-reason distinctions were assessed with a Chi-squared comparison for the two CS groups. There was a statistically significant distinction found between the case group of upper versus lower 50th percentile CSs, where the CSs were based on the TRA CDR3-IE1 antigen, IEDB-51089 (QIKVRVDMV) CSs (Table I) (p=0.02549). The details of these death-reason distinctions are in Table II. There was also a statistically significant distinction between the case groups of upper versus lower 50th percentile CSs, where the CSs were based on the TRA CDR3-UL29 combination (Table I) (p=1e-138), which is detailed in Table III. In particular, the results indicated that the death-reason for the cases in the upper 50th percentile were due to tumor involvement alone rather than toxicity, infection, or tumor and toxicity (Table II and Table III). There were no statistically significant results indicated by the Chi-square test for the TRB-based CSs (Figure 2), however, there were trends (p<0.1) represented by the upper and lower 50th percentile CS groups based on TRB CDR3s (Tables S14, S15). These trends aligned with the statistically significant reason for death, i.e., tumor involvement, as assessed using the TRA CDR3-based CS calculations described above and in Table II and Table III.

View this table:
Table II.

Patient death reasons associated with increased TRA-CDR3-IE1 chemical complementarity.

View this table:
Table III.

Patient death reasons related to TRA-CDR3-UL29 CS groups.

Multivariate analyses. To determine whether any common clinical features represented an overlap with the survival distinctions based on the CSs in turned based on the TRA or TRB CDR3s, several multivariate analyses were conducted. First, a multivariate analysis, including the TRB CDR3-pp65 Fragment 6 CSs, showed no statistically significant correlation of age (p=0.679), or Stages II (p=0.431), III (p=0.241), or IV (p=0.303) with OS. Also, in this same multivariate analysis, there was not a statistically significant correlation of event type, when comparing no events versus progression (p=0.899) or no events versus relapse (p=0.909). The DAWT histological classification associated with a reduced OS probability when compared to the FHWT classification (B=−1.848, p<0.001). Finally, the lower 50th Percentile CS group, based on the TRB CDR3-pp65 Fragment 6 CSs, had a statistically significant, higher OS probability when compared to the upper 50th percentile CS group (B factor=1.292, p=0.001) (Table IV). For additional details, and for additional multivariate analyses reflecting other TCR CS results in this report, see Tables S16-S19.

View this table:
Table IV.

Multivariate analysis values for TRB-CDR3-pp65-Fragment 6 CS groups.

Discussion

The results of this report provided evidence that infection by CMV as indicated by TCR CDR3 recombination reads was associated with a decrease in OS probability for Wilms’ Tumor patients. Notably, TRA CDR3 affinities for the IE1 and the UL29 antigens were associated with a lower patient survival rate, and evidence of TRB CDR3 affinities for the IE1 and the pp65 antigens were also associated with decreased survival rates.

The experimental approach utilized in this study has some limitations. For example, it is impossible to determine whether the infection of a patient by a pathogen occurred before or after the manifestation of the tumor, and this study was retrospective as opposed to prospective. Regardless of limitations, this study is consistent with a negative impact of a CMV infection on the outcome of a patient with Wilms’ Tumor. Specifically, the following chemical complementarity analyses confirmed that a higher CDR3-CMV antigen CSs were associated with a lower survival rate: TRA-CDR3-UL29, TRA-CDR3-IE1-Fragment 7, TRB-CDR3-pp65-Fragment 6, and TRB-CDR3-IE2-Fragment 5. In addition, a higher CS for both the TRA and TRB pairings with the IEDB IE1 TCR epitope was associated with a lower OS probability.

The patient death reasons data suggest that the reason for the association of a TCR-CMV response and a worse outcome was not the infection itself leading to death but rather some alteration to the tumor or the body’s response to the tumor that leads to a patients’ death. However, it is possible CMV infections were directly relevant to patient outcomes but simply not detected or confirmed.

The multivariate analysis demonstrated that there was no statistically significant impact of age of patient or event type on OS probability, and it indicated there was a statistically significant impact of histological classification as well as the CS percentile grouping on OS probability. This helps indicate that the patient age and the event type were not confounding variables, and while histological classification does significantly impact the OS probability, that is expected, as the histology is directly related to tumor severity and prognosis. The statistically significant impact of CS percentile grouping help confirm the connection between TCR-CDR3-CMV antigen CSs and OS probability. Overall, the multivariate analysis supports the evidence of CMV infection is directly related to OS probability independent of the potential confounding variables analyzed.

The results warrant a more careful surveillance of CMV in Wilms’ tumor patients, and a prospective study regarding the potential association of CMV infections with a worse Wilms’ tumor outcome could further support the above results, particularly by providing the opportunity to account for potential, additional confounding variables. Other neoplasms should also be assessed for possible CMV involvement in survival outcomes to provide more generalizable data in the role of CMV and neoplasm outcomes.

Acknowledgements

The Authors thank USF research computing and the admin expertise of Ms. Lindsey Dickerson and Ms. Corinne Walters, who assisted with the application procedures for database access.

Footnotes

  • Supplementary Material

    Available at: https://usf.box.com/s/unlafkxvbcmmn4pwucdlw3b4kvsi8vyi; or available at cbioportal.org.

  • Conflicts of Interest

    The Authors have no conflicts of interest with regards to the present study.

  • Authors’ Contributions

    KLR: Conceptualization; Formal analysis; Methodology; Visualization; Writing – review & editing. MJD: Resources; Methodology; Visualization; Software. ECG: Resources; Methodology; Software. DBK: Conceptualization. JJS, TRH, AC, BIC: Resources; Methodology; Software. GB: Conceptualization; Methodology; Project administration; Resources; Supervision; Writing - review & editing.

  • Received May 28, 2024.
  • Revision received July 9, 2024.
  • Accepted July 22, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Worse Wilms’ Tumor Outcomes Associated With Chemical Complementarity for Multiple T-Cell Receptor CDR3-CMV Epitope Pairs
KASEY L. RIGBY, MICHAEL J. DIAZ, ETIENNE C. GOZLAN, DOROTTYA B. KACSOH, JOANNA J. SONG, TABITHA R. HUDOCK, ANDREA CHOBRUTSKIY, BORIS I. CHOBRUTSKIY, GEORGE BLANCK
Cancer Genomics & Proteomics Sep 2024, 21 (5) 439-447; DOI: 10.21873/cgp.20462
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