Yan Cui, Ph.D.
The major research interests of the Cui lab are centered around the cellular and molecular mechanisms by which tumor-host interactions dictate the immunological landscape of the tumor microenvironment (TME), and the development of novel translatable strategies to improve therapeutic outcome via targeting the tumor-host communications. Specifically, there are two research areas that are actively pursuing and they are detailed below.
Cancer associated fibroblasts (CAFs), as specialized fibroblastic stroma in the complexed TME, play crucial roles in shaping the immune landscape of the TME and are pivotal in tumorigenesis, tumor progression, chemoresistance, and metastasis. Clinically, for many tumor types, high CAF abundancy in the TME is associated with more aggressive tumor progression and poor clinical prognosis. Previous studies suggest that CAFs promote tumor progression by providing additional tumor survival and growth factors. Recent studies in our laboratory and others employing mouse tumor models and clinical tumor specimens demonstrate that CAFs also produce many immunoregulatory cytokines, chemokines, and immunosuppressive molecules. Therefore, CAFs represent a highly immunosuppressive cellular compartment in the TME that impede antitumor immunity by exploiting many crucial immune checkpoints, such as the COX2-PGE2 axis and CD73-eADO circuitry, in addition to PD-L1. We are actively investigating the crucial cellular and molecular elements that underscore the immunosuppressive capacity of CAFs to enforce various immune checkpoints, and employing the new findings to develop novel targeted therapeutic strategies inactivating these checkpoints in the TME.
The tumor suppressor p53 (Trp53) is the most frequently mutated/inactivated gene in tumors. Trp53 suppresses tumor development by inducing apoptosis or senescence, which has been known as a major tumor suppression mechanism of p53. Recently, compelling evidence suggests that p53 also suppresses tumorigenesis by regulating other crucial biological functions, including host immune responses. As chronic inflammation plays a vital role in tumor initiation, progression, and metastasis, it is plausible that p53 inactivation/dysfunction promotes tumorigenesis and tumor progression by compromising host immune surveillance and altering tumor milieu to pro-tumor inflammation. Our recent studies provide experimental evidence demonstrating that p53 inactivation in the TME of murine tumor models skews the immunological landscape toward pro-inflammation and pro-tumor progression. Furthermore, we also demonstrate that targeted activation of the p53 pathway in the TME promotes antitumor immunity and improves tumor-free survival. We are currently exploring new strategies of repurposing and/or expanding the application of pharmacological and biological p53 activation/reactivation for tumor treatment that elicits synergistic effects of tumoricidal and antitumor immunity to maximize antitumor efficacy for tumors maintaining wild-type p53, as well as those that incur p53 mutations.