Tumors characterized by limited Th1-type chemokine (e.g.CXCL9 and CXCL10) expression and low frequency of effector tumor infiltrating lymphocytes (TIL) in the microenvironment, render immune-cell-targeted regimens less likely to succeed. In patients with high grade serous ovarian cancer, a polycomb repressive complex 2 (PRC2) protein, enhancer of zeste 2 (EZH2)-based histone H3 lysine 27 trimethylation (H3K27me3) mediates a repression on CXCL9 and CXCL10 expression. It controls effector T cell tumor trafficking and impacts therapeutic efficacy of cancer immune therapy. Thus, epigenetic mechanism (e.g. PRC2) may control the ?hot? vs ?cold? phenotype of cancer and shape immunotherapeutic efficacy. In addition to PRC2, mammalian chromatin remodeler switch/sucrose non-fermentable (SWI/SNF) complexes (also called BAF complex for Brg-/Brama-associated factor complex) are important epigenetic machinery. AT - rich interactive domain-containing protein 1A (ARID1A) is a member of the SWI/SNF complex. Potential immunological role, immune regulatory mechanisms, immune-associated clinical significance, and therapeutic relevance of ARID1A are unknown in human cancer including human ovarian cancer. Our preliminary data show a deficiency in the IFN?-signaling pathway in several ARID1A mutated ovarian clear carcinoma cells and ARID1A is required for intact CXCL9 and CXCL10 expression. Our previous work reveals that PRC2 complex represses CXCL9 and CXCL10 expression in high grade ovarian cancer. Thus, we hypothesize that there may be a dynamic balance between PRC2 (e.g. EZH2) and SWI/SNF (e.g. ARID1A) complexes in the control of IFN?-responsiveness in ovarian cancer. To test this hypothesis, our project is to conduct comprehensive molecular, functional, translational, and clinical research on the nature of effector T cell tumor trafficking and IFN?-pathway in the human ovarian carcinoma microenvironment, and will provide rich opportunities to take our understanding of effector T cell biology in the tumor to a new level of basic and practical application. The application is highly translational.
Our specific aims are:
Aim 1 is to test our hypothesis that ARID1A -signaling circuit controls tumor IFN?-responsiveness in the tumor microenvironment.
Aim 2 is to test our hypothesis that ARID1A -signaling circuit associates with effector T cell tumor trafficking, tumor immunity, and therapy
Patients with ovarian carcinoma are weakly responsive to the PD-L1 and PD-1 pathway blockade. T cell infiltration and IFN?-signaling pathway are key factors determining spontaneous anti-tumor immunity and tumor therapeutic responses to immunotherapy and chemotherapy. Recent studies have started to understand the significance of the cross-talk between oncogenic and immunogenic pathways in defining tumor immune phenotype. Our preliminary data support the notion that SWI/SNF complex and its potential interaction with the PRC2 complex might be a decisive molecular node for cancer IFN?-responsiveness. This will ultimately shape cancer response to immunotherapy and chemotherapy. Based on our understanding of the critical importance of the tumor immune microenvironment in guiding and improving our current immunotherapy, the published information on tumor SWI/SNF and effector T cells, we hypothesize that the human cancer immune microenvironment holds the key to understanding cancer immunotherapy and chemotherapy. Accordingly, we will investigate the cross-talk between T cells and immune signaling in tumor cells and determine the role and mechanisms of this cross-talk in cancer therapy.
