Spatial Compartmentalization of TCR Repertoires Between Primary Melanomas and Sentinel Lymph Nodes Reveals Distinct Clonal Architectures and Shared Antigen Recognition
Curation statements for this article:-
Curated by eLife
eLife Assessment
This study provides a valuable analysis of T cell receptor repertoire organization in paired primary melanomas and sentinel lymph nodes from treatment-naive patients. The evidence for differences in repertoire architecture between these compartments is solid, but the evidence linking TCR sequence features and sequence-based communities to specific tumor antigens, particularly neoantigens, is incomplete. Additional benchmarking and robustness analyses of the community-based approach, together with more cautious interpretation of antigen specificity, would strengthen the study.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Primary tumors and their sentinel lymph nodes are functionally linked sites of anti-tumor immunity, yet how T cell receptor (TCR) repertoires are organized across these compartments remains incompletely understood. We thus performed TCRβ sequencing on paired primary melanoma tumors and sentinel lymph nodes from 24 treatment-naive patients to quantify TCR repertoire diversity and clonal architecture as markers of antigen-driven selection. Primary tumors exhibited markedly reduced TCR diversity and pronounced clonal dominance compared with matched lymph nodes, consistent with selective expansion of tumor-reactive T cells. Tumor-associated clonotypes displayed significantly longer CDR3 sequences driven by increased non-templated nucleotide insertions, a feature associated with neoantigen recognition, and showed biased TRBV and TRBJ gene usage indicative of CD8+ T cell enrichment. Annotation against known melanoma differentiation and cancer testis antigens identified only a small fraction of clonotypes with characterized specificities, and fewer than 10% of these were shared between tumors and lymph nodes, suggesting that most expanded tumor clonotypes recognize patient-specific antigens. To identify shared immune features beyond individual clonotypes, we applied ClustIRR to build a joint graph linking clonotypes across repertoires by CDR3 sequence similarity and detected Communities on the Joint graph (CJs) to uncover recurrent TCR sequence motifs. Differential occupancy analysis identified distinct CJs segregating tumors and lymph nodes, including a limited number of recurrent CJs targeting MART-1 epitopes, while the majority were patient-specific. Together, these data define spatially structured TCR repertoire architectures in human melanoma and establish a scalable framework for interrogating tumor-immune interactions.
Article activity feed
-
eLife Assessment
This study provides a valuable analysis of T cell receptor repertoire organization in paired primary melanomas and sentinel lymph nodes from treatment-naive patients. The evidence for differences in repertoire architecture between these compartments is solid, but the evidence linking TCR sequence features and sequence-based communities to specific tumor antigens, particularly neoantigens, is incomplete. Additional benchmarking and robustness analyses of the community-based approach, together with more cautious interpretation of antigen specificity, would strengthen the study.
-
Joint Public Review:
Kitanovski and colleagues compare TCRβ repertoires from paired primary tumors and sentinel lymph nodes from 24 treatment-naive melanoma patients. The paired design and comprehensive repertoire analyses are important strengths, and the study provides solid evidence for differences between these compartments, including reduced diversity and greater clonal dominance in primary tumors.
The principal limitation is that antigen specificity is inferred from bulk TCRβ sequencing rather than directly demonstrated. Database annotation and sequence similarity are useful for generating hypotheses, but neither an annotated β-chain nor membership in a sequence-similar community establishes antigen specificity. In particular, the absence of a database match should not be interpreted as evidence of neoantigen recognition. Claims …
Joint Public Review:
Kitanovski and colleagues compare TCRβ repertoires from paired primary tumors and sentinel lymph nodes from 24 treatment-naive melanoma patients. The paired design and comprehensive repertoire analyses are important strengths, and the study provides solid evidence for differences between these compartments, including reduced diversity and greater clonal dominance in primary tumors.
The principal limitation is that antigen specificity is inferred from bulk TCRβ sequencing rather than directly demonstrated. Database annotation and sequence similarity are useful for generating hypotheses, but neither an annotated β-chain nor membership in a sequence-similar community establishes antigen specificity. In particular, the absence of a database match should not be interpreted as evidence of neoantigen recognition. Claims concerning neoantigen specificity should therefore be moderated or supported by additional evidence.
The ClustIRR analysis is potentially useful for identifying relationships among predominantly private TCR repertoires, but its added value and robustness require further evaluation. Benchmarking against conventional repertoire-overlap or alternative TCR-similarity approaches, testing sensitivity to key clustering parameters, and determining whether the results are driven by highly abundant communities would substantially strengthen the analysis. HLA genotype and the non-independence of pairwise repertoire comparisons should also be considered when interpreting inter-individual repertoire similarity.
Overall, the study provides a valuable dataset and convincing evidence for spatial differences in melanoma TCR repertoire architecture, while the biological interpretation of individual TCRs and communities in terms of defined antigen or neoantigen recognition remains less well supported.
-
-
-
-