Uncovering the hidden structure of dynamic T cell composition in peripheral blood during cancer immunotherapy: a topic modeling approach

Immune checkpoint inhibitors (ICIs), now mainstays in the treatment of cancer treatment, show great potential but only benefit a subset of patients. A more complete understanding of the immunological mechanisms and pharmacodynamics of ICI in cancer patients will help identify the patients most likely to benefit and will generate knowledge for the development of next-generation ICI regimens. We set out to interrogate the early temporal evolution of T cell populations from longitudinal single-cell flow cytometry data. We developed an innovative statistical and computational approach using a Latent Dirichlet Allocation (LDA) model that extends the concept of topic modeling used in text mining. This powerful unsupervised learning tool allows us to discover compositional topics within immune cell populations that have distinct functional and differentiation states and are biologically and clinically relevant. To illustrate the model’s utility, we analyzed ∼17 million T cells obtained from 138 pre- and on-treatment peripheral blood samples from a cohort of melanoma patients treated with ICIs. We identified three latent dynamic topics: a T-cell exhaustion topic that recapitulates a LAG3+ predominant patient subgroup with poor clinical outcome; a naive topic that shows association with immune-related toxicity; and an immune activation topic that emerges upon ICI treatment. We identified that a patient subgroup with a high baseline of the naïve topic has a higher toxicity grade. While the current application is demonstrated using flow cytometry data, our approach has broader utility and creates a new direction for translating single-cell data into biological and clinical insights. ### Competing Interest Statement M.A.P. reports grants and personal fees from BMS, Merck, Array BioPharma, and Novartis; personal fees from Incyte, NewLink Genetics, and Aduro; and grants from RGenix and Infinity. M.K.C. reports grants from Bristol Myers Squibb for projects outside this manuscript and personal fees from Merck, InCyte, Moderna, ImmunoCore, and AstraZeneca. K.S.P. reports stock ownership in Johnson & Johnson, Pfizer, Catalyst Biotech, and Viking Therapeutics. R.S. reports grants from NCI/NIH, Parker Ins titute for Cancer Immunotherapy/MSK, MSK Society/MSK during the conduct of the study. The other authors declare no outside interests.