Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade

Abstract

The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.

Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors

“…Neck dissections and elective nodal irradiation (ENI) are therefore commonly adopted strategies to decrease regional and distant metastasis 6 . Such targeting of tumor draining lymph nodes (DLNs), a site for T cell immune priming [7][8][9][10][11] , could lead to a considerable decrease in the number of immune cells migrating to the TME for antigen-specific cell kill. Since immunotherapies are inherently reliant on the immune system, and the lymphatics, some have argued that immunotherapies may be more effective without comprehensive neck dissections or ENI [12][13][14] .…”

Metformin keeps CD8+ T cells active and moving in NASH-HCC immunotherapy

“…Moreover, immune checkpoint molecules, including PD-1, have been shown to modulate T-cell motility. 5 However, in addition to similar levels of PD-1, in the case of CD8+ T cells in NASH mice, the reduced motility was independent of chemotaxis or cell adhesion, suggesting a cell-intrinsic mechanism. To better understand the impaired motility of CD8+ T cells, and considering the importance of metabolism in cell motility, an exhaustive transcriptomic characterization focused on metabolic genes was performed.…”

Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?

“…Finally, depending on their differentiation state and level of PD-1 expression, T cells may be affected differently by PD-1 blockade. For instance, discrepancies in the motility of CD4+ and CD8+ T cells following ICI blockade could be explained by their epigenetic profiles [ 54 ]. In particular, TOX and NR4A, which are epigenetic regulators of T cells exhaustion and anergy, are also known to impact immune checkpoint expression [ 55 , 56 ].…”

“…In particular, TOX and NR4A, which are epigenetic regulators of T cells exhaustion and anergy, are also known to impact immune checkpoint expression [ 55 , 56 ]. Interestingly, several studies suggest that PD-1 expression is associated with chronic exposure to antigens due to infections or cancers leading to TOX- and NR4A-dependent immune exhaustion of T cells [ 54 ]. However, the implications of PD-1 engagement and blockade of those T cells considered as exhausted on motility are unclear and would depend on the context (acute vs. chronic state for example).…”