(E-181) Identifying migration states of CD8+ T-cells in tumor microenvironments

Introduction:: Migration is an essential function of cytotoxic T-cells (CD8+ T-cells) response to foreign cells in the body. It allows the CD8+ T-cells to interact with the antigen-presenting cells and other cells of the immune system to recognize the antigen and finally eliminate the foreign cells. Recent advances in cancer immunotherapies aim to tune T-cell migration to optimize their response. The standard process of quantifying cell migration is by calculating the time-averaged mean squared displacement. However, this quantity can be problematic, especially at large times, while it is possible that cells do not exhibit the same migration state along the trajectory. In this study, we postulate a statistical framework to analyze CD8+ T-cell migration in tumor microenvironments. We use position data of T-cells in melanoma tumors with respect to time, collected with two-photon microscopy to identify the migration states of the T-cells based on their cell motility and quantify the transition rates between the states. Our results suggest that CD8+ T-cells exhibit a fast and slow-moving state, and they dynamically switch between them.


Materials and Methods:: Tumors from 4 mice were harvested and two-photon microscopy was performed. CD8+ T-cells were stimulated with Interleukin-12 (IL-12) to prevent exhaustion. The cell tracking data was acquired with Imaris software. A Gaussian mixture model (GMM) was used to classify the states based on the distribution of the displacements and Akaike and Bayesian Information Criteria was used to identify the number of states. After the identification of the number of states, a Hidden Markov Model (HMM) was fitted to infer the transition probabilities between the states.


Results, Conclusions, and Discussions:: Our results, based on the Gaussian Mixture Model, suggest that CD8+ T-cells exhibit two migratory states, one slow and one fast-moving state, which agrees with the current literature. However, T-cells do not stay in one of the two states solely, but they dynamically switch between the two of them. The switching is more intense in the low-avidity T-cells because of their lower strength to bind to the target cells, compared to the high-avidity T-cells.


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