State: Oregon

Dendritic cells are a type of immune cell that patrols tissues to find signs of disease. When they find a tumor, they can pick up pieces of multiple different cell types including normal cells, bacteria, and pieces of the tumor called antigens. Their main job is to carry these tumor antigens to special T cells that can kill tumors. They show the antigens to the T cells to let them know there is cancer in the body and guide the T cells to attack the tumor. In places like the skin, dendritic cells can pick up both harmless skin antigens and dangerous melanoma tumor antigens at the same time. This is tricky because dendritic cells need to show the harmful melanoma antigens to T cells to fight the cancer, but they also have to hide the harmless skin antigens from T cells so they don’t mistakenly attack healthy tissue. Our research shows that when dendritic cells take in many different types of antigens at once, it’s harder for them to tell the T cells about the tumor. This can weaken the immune system’s response to cancer. We are studying how dendritic cells can better separate these antigens to improve how they activate T cells against melanoma. Our goal is to use this knowledge to create better treatments that boost the immune system’s ability to fight cancer. This could lead to more effective therapies that protect normal tissues and strengthen the immune response against tumors.

Volunteer Grant funded by the V Foundation Wine Celebration in honor of Paul Dugoni and in memory of Lynn Dugoni

Cancer immune therapies that trigger the body’s own immune system to fight tumors have greatly improved cancer treatment over the last 10 years. Still, most patients do not benefit from this approach for reasons that remain unclear. The goal of our work is to determine what prevents the immune system from fighting cancer in order to design better immune therapies that can help more patients. Our studies focus on T cells, the immune cell type that plays the biggest role in killing tumor cells. T cells can kill cancer cells because cancer cells have mutations that T cells see as dangerous to the body. In theory, T cells that see different mutations should be able to work together to control tumors. However, our research has shown that T cells compete with each other to fight tumors and this greatly reduces the effectiveness of the T cell response. T cell competition may explain why some patients do not respond well to immune therapies. Our work is aimed at understanding why T cell competition occurs so that we can design immune therapies that promote T cooperation to better fight tumors. Our research will explore cancer vaccines as one potential treatment approach. We focus our studies on lung cancer, which causes the most cancer deaths each year, though we expect our results will be relevant to many cancer types. Findings from our work will allow development of more effective immune therapies for cancer patients that will decrease suffering from this terrible disease.

Liquor, tobacco and human papilloma virus (HPV) infection are major causes of head and neck cancer (HNC). Adult males often contract HPV infection via oral sex. People carrying HPV are at higher risk of developing HNC. Current HPV vaccines do not work in people already infected or in cancer patients. In the U.S., one in four persons are HPV positive. Thus, HNC will remain an important health problem for decades because of the high number of currently infected people. The major goal of our research is to design a cancer vaccine that works after disease onset.

Vaccination works by prodding the immune system to make protective antibodies. Our previous research suggests that antibodies against tumors are present for a short time as cancer grows. Now, we aim to learn how antibodies against tumors are made. We will use this knowledge to develop safe vaccine therapies to cure existing disease. Our approach is different because current immune therapies target cellular immunity, that is T cells, whereas we aim to exploit humoral immunity, that is B cells and antibodies.

This work will provide key data to push a patient’s immune system to make more anti-cancer antibodies and cure their disease. These new therapies will avoid marring head and neck surgeries and thus will improve how patients function. Importantly, our therapeutic approach can be extended to any type of cancer.

Funded by Team V runner Jack Daly’s fundraising efforts in loving memory of his wife, Bonnie

In 2016, pancreatic cancer overtook breast cancer to become the third leading cause of cancer related death in the United States.  Therapies used to treat pancreatic cancer to date have provided limited benefit, indicating that an improved understanding of complex mechanisms of disease progression are needed to develop more effective therapeutic strategies.  Pancreatic cancer is characterized in part by an exuberant fibrotic and inflammatory reaction which infiltrates and surrounds tumors, together known as the tumor microenvironment.  The pancreatic tumor microenvironment both creates a harsh environment for cancer cells to grow, by limiting blood flow and nutrient availability within the tumor, but also provides factors that enable cancer cells to survive and adapt in the context of this nutrient-poor, challenging microenvironment.  I hypothesize that particular cells within the pancreatic tumor microenvironment known as stellate cells, have evolved mechanisms to “feed” energy to cancer cells to simultaneously promote their survival and growth, and to regulate expression of cancer-supportive genes.  To test this hypothesis, I will use a combination of patient-derived cancer and microenvironmental cells; these cell types will be cultured together to understand on a molecular level the impact of supportive cells on pancreatic cancer cell survival and behavior.  These mechanistic studies will be accompanied by investigation of relevant metabolic pathways in mouse models of human pancreatic cancer, testing both genes and pharmacologic agents which may inhibit microenvironment-mediated tumor growth.  Together, these studies have the potential to identify a novel metabolic liability of pancreatic cancer, which may be targetable for therapeutic benefit.

If detected early melanoma is usually curable with surgery. However, melanomas are often detected at later stages after cancer cells have metastasized and survival rates for patients with metastatic disease are less than 15%. Furthermore, some thin melanomas, even when detected early, lead to mortality. What defines this difference in outcome is largely unknown and suggests a need for new markers that can predict a patient’s risk. Recently, the cellular microenvironment that surrounds a tumor has gained significant attention as a critical regulator of tumor progression, response to therapy and resistance. Effective therapies that specifically target immune suppression by tumor microenvironments have been developed; however, our understanding of the specific way in which these therapies work is incomplete. A better understanding of which parts of the microenvironment suppress immune responses will not only allow for better prediction of patient prognosis but may also help enhance a patient’s response to new immune-based therapies. Lymphatic vessel growth in melanoma is correlated with poor prognosis and enhanced metastasis to lymph nodes, however, until now lymphatic vessels were largely ignored as players in host anti-tumor immune responses. Our recent work demonstrates for the first time that lymphatic vessels are immune suppressive in tumor microenvironments and impair therapy. This proposal will test the hypothesis that lymphatic vessels directly contribute to immune suppression and suggests they may be a novel marker both for risk stratification in melanoma patients and as a novel therapeutic target.