Chronic inflammation increases cancer risk and accelerates the progression of many malignancies, including those of the lung, stomach, liver and colon. Pro-inflammatory cytokines and tumor-infiltrating myeloid and immune cells play critical roles in all stages of cancer development. Immune infiltrates are evident in most if not all solid tumors, including those that exhibit no pre-cancer inflammation. It is now clear that the process of tumorigenesis leads to changes in tumor cells and their microenvironment. Such changes shape the quality and magnitude of immune responses to tumors, resulting in the activation of tumor-promoting inflammation and suppression of anti-tumor immunity. The nature of tumor-immune interaction is therefore under intensive study in hope to understand how cancers arise and evolve, and how we can develop novel diagnostic and therapeutic tools for the benefit of human cancer patients.
Research in my lab focuses on the role of interleukin-17 (IL-17) family cytokines in colorectal cancer development and therapeutic intervention. IL-17 plays important roles in immunity against invading pathogens and in chronic inflammation of autoimmune diseases. IL-17 signaling also drives the development of colorectal, breast, pancreatic, and prostate cancers. Our and other people’s previous studies have shown that IL-17 signals to both tumor cells and their environment. Direct engagement of IL-17 promotes tumor cell proliferation and survival, whereas IL-17 signaling on stromal and immune cells seems to promote tumor-associated inflammation and suppress anti-tumor immunity. Despite these breakthroughs, the mechanism by which IL-17 regulates tumor inflammation and immunity response remained largely elusive.
Our current study aims to answer the following questions:
1) What is the relationship between IL-17 mediated inflammation and anti-tumor immunity?
2) How does IL-17 regulate tumor associated inflammation and immunity?
3) Can we improve the efficacy of anti-cancer chemotherapy and immune therapy by inhibiting IL-17?
By addressing these questions, we hope to provide additional insight on the interaction between tumor cells and their environment, and develop more effective anti-cancer therapies for the benefit of human health.
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Our research aims to understand the role of IL-17 in the development, immune regulation, and treatment of colorectal cancer. The study is comprised of the following projects:
1) Define the relationship between IL-17-mediated inflammation and anti-tumor immunity: Our previous study showed that IL-17 is significantly up-regulated in colonic tumors compared to adjacent normal colon tissues during early phase of colorectal cancer development. Ablation of IL-17RA, a receptor for IL-17, resulted in marked reduction in colorectal tumor burden, suggesting a strong tumor-promoting role of IL-17 in the colon. In addition to the direct tumor promoting function of IL-17, we also found that IL-17 suppresses the recruitment and activation of cytotoxic T lymphocytes (CTLs) in tumor. In this project we will perform in-depth examination on the role of IL-17 in regulating the recruitment and activation of anti-tumor immunity.
2) Elucidate the mechanism by which IL-17 regulates tumor associated inflammation and immunity: IL-17 is known to promote inflammation and in the case of cancer, inhibit anti-tumor immunity. However the underlying mechanism remained unclear. Using our newly developed Il17ra-flox mice, we will ablate IL-17 signaling in different immune and stromal cells and search for the cellular target of IL-17 signaling in the process of inflammation and immune modulation.
3) Blocking IL-17 as an adjuvant therapy for the treatment of colorectal cancer: We have shown that IL-17 drives the outgrowth of micro-adenomas into large tumors in the gut. Antibody-mediated long-term neutralization of IL-17A resulted in reduced tumor burden. When combined with traditional chemotherapeutic agent 5-fluorouricil (5-FU), IL-17A neutralization improved the outcome of chemotherapy against established colorectal tumors. In the current study, we plan to test the combination of IL-17A or IL-17RA antibodies to different chemotherapeutic agents, including 5-FU, irinotecan and oxaliplatin. In addition, we will combine anti-IL-17 treatment with immune-checkpoint blockers and co-stimulation agonists to test if the inhibition of tumor-associated inflammation can improve the efficacy and/or safety of cancer immune therapy.