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CD8+ T cells are critical in both cancer and chronic infection. The course of the diseases is related to how effective they are at eliciting appropriate immune responses. Exploring the mechanism that could avoid CD8+ T cells from exhaustion has become one of the breakthroughs in immunotherapy against different malignancies. The main challenge, however, is that only a small percentage of patients experienced a complete response. As a result, understanding the fundamental process of how CD8+ T cell exhaustion is regulated is crucial in attempts to correct the dysfunctional condition of CD8+ T cells. DNA Damage Response (DDR) has been investigated as a targeting pathway for killing cancer cells by exploiting more DNA damage in cancer cells than repairs. However, how DDR acts on immune cells, especially in CD8+ T cell exhaustion, is still far from clear. Therefore, the study is aimed to investigate the role of DDR in CD8+ T cell exhaustion by using a multi-omics approach. In transcriptomic analysis, DDR was upregulated in addition to well-established genes related to CD8+ T cell exhaustion as tumor progress. Moreover, DDR was specifically activated in critical period, which is in the transition to terminal exhaustion. These findings are consistent across multiple cancer types. In proteomic analysis, ATR kinase was first activated and then followed by ATM kinase during the progression of CD8+ T cell exhaustion. In addition, in vitro functional assays were performed to show the causal relationship between DDR and CD8+ T cell exhaustion, pointing out the role of ATM kinase as a checkpoint for this event. Subsequently, DDR- activated exhausted CD8+ T cells were enriched in specific neighborhoods that are also abundant with myeloid niches where PD1-PDL1 signaling pathway established as shown in multiplexed imaging analysis. In addition, myeloid milieu-coordinated PD1-PDL1 signaling pathway was responsible for the DDR-associated exhaustion of CD8+ T cells. Finally, the L- R signature as a result of DDR-activated exhausted CD8+ T cells and PDL1-high myeloid cells interaction enabled predicting the prognosis and the clinical responses of patients receiving immune checkpoint inhibitor. In summary, our study provides a better understanding of CD8+ T cell exhaustion with potential for new strategies to stratify patients and design combinations of immunotherapies.

Keywords: DDR, Exhaustion, CD8+ T cells, Multi-omics approach, Immunotherapy

Taiwan International Graduate Program in Molecular Medicine,
National Yang-Ming University and Academia Sinica
Doctoral Dissertation