Program control of CD8+ T cell response to tumors and tumor memory - Abstract CD8+ tumor infiltrating lymphocytes (TILs) are not only critical for the anti-tumor immune response in solid tumors, but also in the success of adoptive cell therapies and in immune check point blockade (ICB) treatments. CD8+ TILs have been shown to be heterogeneous, and in time to progress to a terminally exhausted state, with no ability to respond, and resistant to reprograming by ICB. It remains of critical importance to understand the biology, transcriptional programs and epigenetic control of the progression of the precursors, which have high functional potential and stemness, to the terminally exhausted CD8+ TILs. Cells with characteristics of memory have been identified in tumors and their presence is associated with a positive outcome. Recently a memory CD8+ T cell population has been identified, located predominantly in tumor draining LNs and showing an efficient antitumor response upon recall. However, little it is known about tumor memory cells, their response, transcriptional and epigenetic control, as well as their failure in recurrent tumors associated with relapse. Our preliminary data show that ablation of the transcription factor BCL11B in TILs unleashes stemness at the same time with the effector programs, but restricts exhaustion, providing TILs with increased ability to promote a more efficient anti-tumor response compared to WT counterparts. In addition, depletion of BCL11B in TILs from a patient who did not respond to TIL adoptive cell therapy, improved their cytolytic activity. We hypothesize that BCL11B plays a central role in controlling essential programs of TILs, including stemness, effector and exhaustion. Our preliminary data also show BCL11B KO tumor memory cells outperform WT memory cells in a recall response to tumors. Using scRNAseq and genome-wide histone marks analyses we will establish the programs and epigenomic landscape controlled by BCL11B in mouse TILs. In addition, we will investigate the programs and the epigenomes in melanoma TILs from responders and non-responders to TIL ACT, as well as from ovarian TILs form newly diagnosed and recurrent ovarian cancer patients. We will determine the differences in their programs and epigenome and the dependence on BCL11B, as well as the impact of BCL11B depletion on anti-tumor activity. We will also investigate the heterogeneity and transcriptional programs of tumor memory cells, their dependence on BCL11B and the behavior of the tumor memory cells in the recall response. We will employ a multimodal integration strategy, to establish the pathways, the regulatory networks and regulomes controlled by BCL11B in human and mouse TILs. Further the knowledge gained, including the BCL11B KO signature and BCL11B regulatory networks, will be employed to predict the response to treatments, including to ICB, and overall patient survival.
