Short-Term Clonal Remodeling in Intratumoral TCR Repertoires Despite Stable Global Diversity

23 Apr 20264 min read0 viewsJournal Feed

GIST

BackgroundTumor-infiltrating T cell receptor repertoires are increasingly profiled to assess intratumoral T cell dynamics and inform prognosis and treatment response. Most analyzes rely on aggregate diversity metrics, such as Shannon index or clonality, which describe overall repertoire structure but do not resolve changes in clonotype identity over time.

Thus, intrinsic temporal dynamics of intratumoral T cell receptor repertoires during tumor progression remain incompletely defined.MethodsIn a bilateral murine cancer model, one tumor was surgically removed, and the paired tumor was collected 11 days later. The T cell receptor repertoires of these tumors, and of synchronously harvested bilateral tumors from separate control animals, were analyzed using diversity metrics, Morisita–Horn similarity, and clonal tracking approaches.ResultsTime-matched bilateral tumors exhibited highly similar clonotype composition and abundance.

In contrast, time-separated tumors showed reduced clonal overlap, increased fractions of private clonotypes, and redistribution of dominant clones. These changes occurred despite preserved global repertoire metrics, including clonotype number, Shannon diversity, and Gini coefficient.ConclusionShort-term tumor progression is associated with clear changes in the composition of the intratumoral T cell receptor repertoire, even when overall diversity appears stable.

Clinical Editorial

Context and design

Control animals contributed time-matched bilateral tumors.

The study investigates how intratumoral T cell receptor (TCR) repertoires change over short intervals during tumor progression.
A bilateral tumor setup was used: one tumor from each mouse was resected, while the opposite lesion was collected 11 days later.
Analyses focused on clonotype identity over time, using diversity metrics, Morisita–Horn similarity, and clonal-tracking methods.

Key observations on clonal dynamics

Time-matched bilateral tumors displayed high concordance in clonotype composition and abundance.
Time-separated tumors differed markedly, with reduced clonal overlap and an increase in private clonotypes, accompanied by redistribution of dominant clones.
These shifts occurred even when global repertoire metrics remained stable, including clone count, Shannon diversity, and Gini coefficient.

Interpretive implications

Short-term tumor progression is associated with meaningful remodeling at the level of individual clonotypes, despite preserved aggregate diversity.
Reliance on global diversity indices alone may conceal underlying clonal rearrangements shaping the intratumoral TCR landscape.

Limitations and reporting notes

The study presents data from a specific bilateral murine model with an 11-day interval; extrapolation to other models or longer time frames should be cautious.
Explicitly, the analysis does not rely on or report outcomes beyond the observed stability of global diversity metrics in the face of clonotype-level changes.