Chronic inflammatory signals have been shown for their roles in promoting progression of nascent tumors. However, it is unclear how inflammatory signals may trigger early transformative events that even precede mutagenic hits. It is the study of stomach (or gastric) cancer that has provided some of the initial evidence for a role of inflammation in oncogenesis. Extensive studies have established Helicobacter pylori as a major environmental risk factor for stomach cancer. A few host-genetic risk factors are identified. Recent studies have showed that patients with CTLA4 haplo-insufficiency or genetically-predisposed CTLA4 insufficiency have a high risk of stomach cancer development. Although these recent data are paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity, the genetic evidence suggests new pathways of tumorigenesis and reflects the inflammatory etiology of human stomach cancer in general. We have created a murine model of CTLA4 insufficiency called CTLA4 RNAi knockdown (CTLA4KD) model. In the CTLA4KD model, immune dysregulation and inflammation in the stomach lead to spontaneous initiation of stomach cancer. This process is associated with aberrant inflammatory cytokine production and age-associated epigenetic dysregulation. The CTLA4KD model not only mimics stomach cancer initiation by CTLA4 insufficiency, but also captures the general feature of pathological progression in inflammation-driven cancer development. Therefore, this model can be instrumental for identifying novel interventions against cancer development in the stomach and other organs.

On the other hand, clinical data from cancer immune therapies suggest that autoimmunity elicited from blocking immune checkpoints such as CTLA4 or PD-1/PD-L1 may contribute to the destruction of tumors. Our studies with breast cancer, insulinoma or lymphoma models suggest that autoimmunity may indeed be tackled as an effective tumor-killing mechanism. Thus, understanding the complexity and paradox in the relationship of autoimmunity, inflammation and cancer will advance the long-term goal of improving cancer immunotherapy, while minimizing the hazards of immune-mediated tissue damage and the risks of inflammatory oncogenesis, through proper monitoring and preventive interventions. In summary, our team focuses on developing novel animal models to dissect the autoimmunity implications in antitumor immunity, and use the models to tackle the mechanisms by which inflammatory signals derived from immune cells kill tumors or promote tumor initiation and progression. Along this line, we also collaborate with computational biologists to identify novel biomarkers, with a particular focus on genome-wide search of splice variants associated with diversification of cancer transcriptome and evolution of cancer cells.

Selected Publications:

1. Miska J, Bas E, Devarajan P, Chen Z (2012). Autoimmunity-mediated antitumor immunity: tumor as an immunoprivileged self. Eur J Immunol. 42: 2584-2596. PMID: 22777737.
2. Miska J, Devarajan P, Chen Z. (2013). The immunological identity of tumor: self implications. OncoImmunology. 2: e23794. PMID: 23734327.
3. Toomer KH, Chen Z (2014).  Autoimmunity as a double agent in tumor killing and cancer promotion. Front Immunol.  5:116. PMID: 24672527.
4. Wen J, Toomer KH, *Chen Z, *Cai X  (*co-senior authors) (2015). Genome-wide analysis of alternative transcripts in human breast cancer. Breast Cancer Res Treat.151:295-307. PMID: 25913416.
5. Miska J., Lui JB, Toomer KH, Devarajan P, Cai X, Houghtonm J, Lopez DM, Abreu MT, Wang G, and Chen Z (2018). Initiation of Inflammatory Tumorigenesis by CTLA4 Insufficiency Due to Type 2 Cytokines. J Exp Med. 215(3):841-858. PMID: 29374027.