Investigating the molecular and cellular mechanisms of virus-associated hepatocellular carcinoma

PROJECT SUMMARY/ABSTRACT Cancer development accompanies with the dynamic evolution of immunity, a well-­known process termed as immunoediting. However, the underlying mechanisms of the transition between each phase, from immune surveillance to final escape, still remain a lot to discover. This proposal aims to study immunoediting during liver cancer development and progression, with a focus on senescence and metastasis. Senescence is a cell cycle arrest program that limits the expansion of damaged cells and can trigger anti-­tumor immunity that leads to their elimination in vivo, serving as a potent barrier to tumorigenesis. However, during tumor initiation, the effective clearance of senescent cells is compromised, warranting a deeper mechanistic understanding of this process. My doctoral research aims to identify critical molecular and cellular players driving anti-­tumor immune responses during senescence surveillance triggered by wildtype p53, which is known to modulates cancer immunity. The long-­term objective of my thesis project is to define the mechanisms of how senescent cells are susceptible to immune surveillance and how these mechanisms are evaded or bypassed during cancer development and progression. As described in Specific Aims 1.1-­1.3, my thesis work has demonstrated that the p53 restoration triggers regression of liver cancers in an immunocompetent host. Using different immunodeficient mouse strains and pharmacological approaches perturbing specific immune compartments, our preliminary data suggests that adaptive immunity plays a key role in senescence surveillance. RNA-­seq and mass spectrometry were conducted on both proliferating and senescent tumor cells and revealed several senescence-­enriched cell surface factors related to epithelial-­immune cell interactions. In Specific Aims 1.4 and 1.5, we aim to functionally interrogate the role of these senescence-­induced factors as novel senescence surveillance effectors, with a focus on the regulatory network of antigen presentation pathway and, by exploiting multiplexed in vivo genetic screens established in the Lowe laboratory. My postdoctoral research will continue to study immunoediting with a slight change of the focus from the epithelial-­tumor angle to a more immunology-­rich perspective, applied to the problem of metastatic immune escape. The proposal aims to investigate the molecular changes of NK cells, shown to have control of early metastasis, after having physical interaction with metastatic cells. During different stages of metastatic colonization, tumor-­engaging NK cells are labeled via “SynNotch” technology and will be subjected to single-­cell RNA-­seq to unveil the NK cell heterogeneity (Specific Aim 2.1) and ATAC-­seq to reveal potential epigenetic mechanisms of immune exhaustion with functional perturbation of the altered programs employed (Specific Aim 2.2). The proposed postdoctoral research will increase our mechanistic understanding of NK biology during the metastasis outbreak, paving new paths to harness innate immunity against cancer. In all, these two projects will offer distinct insight into immunoediting, of which the elucidated mechanisms could be exploited for developing novel immunotherapies, jointly with existing ones for more effective cancer control.