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

TL;DR

This paper introduces a Bayesian longitudinal mixture model for analyzing TCR clonotype expansion in cancer patients, revealing associations with prognosis, therapy, and genetic features, improving upon traditional methods.

Contribution

It presents a novel Bayesian model that handles variable follow-up and missing data, enabling more accurate identification of expanding TCR clones and their biological characteristics.

Findings

Increased TCR clone expansion in metastasis-directed therapy patients

Associations between clone expansion and disease progression

Distinct receptor motifs and VJ gene enrichments in expanding clones

Abstract

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. 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 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.