Spatial determinants of CD8+ T cell differentiation in cancer

CD8+ T cells in tumors are heterogenous and comprise multiple differentiation states. Deep proteomic and transcriptomic profiling of these cells has been achieved, while spatial information on where these cells localize within tissues has lagged. Imaging technologies have uncovered intra-tumoral niches that house these cells, along with tertiary lymphoid structures that may act as immune hubs within tumor tissues. Recent studies also highlight the importance of the tumor-draining lymph node in shaping antitumor effector responses. New multiplex imaging or spatial transcriptomics technology can further elucidate cellular interactions to inform new cancer therapeutics. Uncovering the mechanisms that control CD8+ T cell function is a major focus of cancer research. Advances in flow cytometry and single-cell transcriptomics have provided unprecedented in-depth resolution of CD8+ T cell states in cancer. However, these technologies fail to capture important spatial information, including cell–cell interactions and tissue localization. The discovery that intra-tumoral immune niches, tertiary lymphoid structures, and the tumor-draining lymph node are key sites of inter-cellular communication has evoked interest in understanding the spatial determinants that regulate CD8+ T cell functions at these sites. We focus on the cellular, as well as the soluble and surface-bound signals that regulate CD8+ T cell phenotypes and functions in a topologically-regulated manner, highlighting where new spatial transcriptomics and imaging technologies can uncover mechanistic insights. Uncovering the mechanisms that control CD8+ T cell function is a major focus of cancer research. Advances in flow cytometry and single-cell transcriptomics have provided unprecedented in-depth resolution of CD8+ T cell states in cancer. However, these technologies fail to capture important spatial information, including cell–cell interactions and tissue localization. The discovery that intra-tumoral immune niches, tertiary lymphoid structures, and the tumor-draining lymph node are key sites of inter-cellular communication has evoked interest in understanding the spatial determinants that regulate CD8+ T cell functions at these sites. We focus on the cellular, as well as the soluble and surface-bound signals that regulate CD8+ T cell phenotypes and functions in a topologically-regulated manner, highlighting where new spatial transcriptomics and imaging technologies can uncover mechanistic insights. cells that can process and present protein antigens as peptides loaded onto MHC molecules and activate T cells. Dendritic cells, macrophages, and B cells are APCs. cytokines that have chemotactic activity once bound to their cognate cell surface receptors and mediate cell migration and positioning. T cell surface receptors that negatively regulate T cell receptor-triggered signals that are highly expressed on dysfunctional CD8+ T cells. Examples include PD1, Tim3, Lag3, and Tigit. hot tumors have a high immune infiltrate, including CD8+ T cells, while cold tumors have little to no immune cell infiltration. the secondary signal (after the TCR signal) provided by APCs that is necessary for T cell activation. For example, APCs provide co-stimulation to CD8+ T cells through the expression of B7 molecules that bind to CD28 on the surface of T cells. structures that arise in secondary lymphoid organs and TLS where activated B cells proliferate and undergo somatic hypermutation to become antibody-secreting plasma cells. immunotherapy that uses antibodies to inhibit the interaction between a checkpoint receptor and its ligand. Examples include anti-PD1, anti-PDL1, and anti-CTLA4 therapy. a fluorescent imaging technique where imaging windows are placed in live animals and tissues are imaged over a period of time to study cell dynamics in their native environment. technologies that measure transcriptomic (mRNA expression) information while preserving spatial information allowing for mapping of gene expression information back to cellular location in tissue. the lymph node immediately downstream of the tumor where lymph generated from the tumor, containing free antigen and antigen-loaded dendritic cells, is drained via the lymphatic system.