Identifying expanding TCR clonotypes with a longitudinal Bayesian mixture model and their associations with cancer patient prognosis, metastasis-directed therapy, and VJ gene enrichment

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Abstract Motivation Examination of T cell receptor (TCR) clonality has become a way of understanding immunologic response to cancer and its interventions in recent years. An aspect of these analyses is determining which receptors expand or contract statistically significantly as a function of an exogenous perturbation such as therapeutic intervention. Results We characterize the commonly used Fisher’s exact test approach for such analyses and propose an alternative formulation that does not necessitate pairwise, within-patient comparisons. We develop this flexible Bayesian longitudinal mixture model that accommodates variable length patient followup and handles missingness where present, not omitting data in estimation because of structural practicalities. Once clones are partitioned by the model into dynamic (expanding or contracting) and static categories, one can associate their counts or other characteristics with disease state, interventions, baseline biomarkers, and patient prognosis. We apply these developments to a cohort of prostate cancer patients who underwent randomized metastasis-directed therapy or not. Our analyses reveal a significant increase in clonal expansions among metastasis-directed therapy (MDT) patients and their association with later progressions both independent and within strata of MDT. Analysis of receptor motifs and VJ gene enrichment combinations using a high-dimensional penalized log-linear model we develop also suggests distinct biological characteristics of expanding clones, with and without inducement by MDT. Availability and Implementation An example model implementation in R/STAN is available at doi.org/10.5281/zenodo.21209546 Supplementary Information Supplementary material includes simulation results, longitudinal mixture model component derivation, HLA typing analysis, and stability selection for the VJ gene family.