New Approaches to Interrogate T Cell Differentiation in Tissue and Tumor, and the Consequences For Immune Protection
Access to this document is restricted. Some items have been embargoed at the request of the author, but will be made publicly available after the "No Access Until" date.
During the embargo period, you may request access to the item by clicking the link to the restricted file(s) and completing the request form. If we have contact information for a Cornell author, we will contact the author and request permission to provide access. If we do not have contact information for a Cornell author, or the author denies or does not respond to our inquiry, we will not be able to provide access. For more information, review our policies for restricted content.
CD8+ T cells are critical participants in antitumoral immunity and are target cells for many immunotherapies. To improve patient responses, there is a need for better tools to classify CD8+ tumor infiltrating lymphocytes (TILs), especially as many current studies mistakenly classify TILs based on individual markers such as PD-1, which are expressed by multiple lineages – exhausted CD8+ T cells and resident memory T cells (TRM). We applied functional genomics, interrogating 9000 human tumors and multiple single-cell sequencing datasets. We attempted to use more unbiased classification methods, leveraging gene signatures and kinetic datasets of benchmark T cell differentiation to assign TILs status. Doing so we found that CD8+ TILs could best be transcriptionally modelled along an activation to memory trajectory. TILs clusters increased in immune checkpoint blockade (ICB) non-responder associated samples overlapped early viral activation, rather than terminal exhaustion. In contrast, TILs associated with response to ICB scored for long term memory and TRM. Finally, we found that persistent memory and TRM, but not activation signatures stratified melanoma survival, and correlated with each other and dendritic cell signatures. Another outcome of ICB is the emergence of immune related adverse events (irAE), autoimmune effects that can lead to treatment discontinuation. However, incidence of irAE, particularly in skin, predict ICB responsiveness. Therefore, we also sought to transcriptionally characterize cutaneous irAE. Doing so we found that cutaneous irAE exhibited increased immune and CD8+ T cell infiltration, with our results suggesting that the differentiation of CD8+ T cell might drive irAE incidence, like in tumor. Finally, we found that cutaneous irAE overlapped gene signatures of atopic and contact dermatitis, dermatoses associated with CD8+ TRM. Lastly, given the relevance of TRM to ICB responses and irAE, we analyzed how PD-1 affected TRM programing. Transcriptional analysis suggested PD-1 deficient T cells were unable to silence other states and sense local cues such as TGFb. Taken together, these data suggest that promoting memory/TRM differentiation may both improve ICB responses and drive pathogenesis of cutaneous irAE, as well as characterize levers that affect TRM formation.