Although high-grade serous ovarian cancer is a challenging disease with unacceptably high mortality, about a quarter of patients "beat the odds" and live for many years after treatment. Why do some patients do so well? In the past 10 years, it has become well established that some ovarian cancer patients mount strong immune responses against their tumor. Tumors from such patients are densely packed with "killer T cells," a type of white blood cell that fights viral and bacterial infections, as well as cancer. Importantly, patients with large numbers of killer T cells in their tumor have markedly higher survival rates. This is a very promising and exciting finding, as it shows that the immune system can have a profound influence on survival from ovarian cancer. Our team is dedicated to understanding the immune response to ovarian cancer so that we can design new forms of treatment to enhance this natural defense mechanism.

Summary of Original Idea Project: Killer T cells have very specific receptors that can recognize proteins expressed by cells. Because ovarian cancers are known to express a lot of mutated proteins, we reasoned that killer T cells might recognize these mutations as "foreign" and launch an attack against the tumor. As part of our original Idea Project (funded in 2008), we have used the most advanced DNA sequencing methods to identify the mutations present in tumors from three ovarian cancer patients. We have also assessed how mutations change over time as patients go through treatment and recurrence. Our results so far indicate that the average ovarian tumor contains about 50 so-called "point mutations." Additional mutations are found in recurrent tumors, indicating that the tumor is evolving over time. We are currently testing whether killer T cells from these patients recognize the mutations we have found. If so, then in future we envision being able to make vaccines or other forms of treatment that help killer T cells recognize tumor mutations to ensure they mount a strong response against the tumor.

Proposed Teal Expansion Project: While killer T cells are clearly important players in the immune response to ovarian cancer, in the past few years we have discovered that two other types of immune cell play an important supportive role: B cells and helper T cells (specifically, helper T cells that express a protein called FoxP3). We made this discovery by performing a systematic analysis of immune cells in ovarian cancer. We found that killer T cells are often found in small clusters together with B cells and helper T cells. Importantly, we found that patients whose tumors have these combinations of immune cells have better survival rates than patients whose tumors contain killer T cells alone. This tells us that killer T cells do not work in isolation. Rather, they are part of a network or circuit of immune cells that work together to attack the tumor. These findings have powerful clinical implications: To enhance the immune response to ovarian cancer, we need to enhance the activity of all three types of immune cell, rather than killer T cells alone. As a first step toward this goal, we need to understand how these immune cells work together. Drawing on findings from the autoimmunity field, we hypothesize that B cells may serve as "organizers" that help to draw T cells into the tumor. B cells also might present tumor proteins to the T cells to facilitate tumor recognition. We further hypothesize that FoxP3 helper T cells might produce cytokines (chemical messengers) that help to excite the killer T cells. To test these hypotheses, we propose to determine which tumor proteins (antigens) are recognized by B cells and FoxP3 helper T cells in ovarian cancer. By identifying these antigens, we will be able to create new molecular tools to elucidate how the immune system recognizes and attacks ovarian cancer.

Significance: The immune system has a profound influence on survival from ovarian cancer. With better understanding of the immune response, it will be possible to design new treatments such as vaccines that enhance tumor immunity and increase patient survival. To do this intelligently, we need to better understand how the immune response works. Which immune cells are important, which features of the tumor do they recognize, and how do they work together? Together, our original Idea Project and Teal Expansion Project will answer these questions for three of the most important immune cells in ovarian cancer. We envision our work will lead to a major re-think about cancer vaccines: Instead of simply trying to activate killer T cells, we also need to find effective ways to activate their teammates, the B cells and FoxP3 helper T cells.