Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Our immune systems are internal barometers for the primary response to foreign invaders like viruses and bacteria within our body. Despite cancer arising from irregular growth of our own cells, the immune system can effectively kill cancer cells just as it identifies and kills infected cells. However, cancer can also effectively hide from the immune response (known as immune evasion), specifically because it grows from our normal cells becoming mutated or unchecked. Thus, preventing immune evasion and augmenting the immune response are now the focus of new and promising treatments. The immune cells found in cancer can be classified by function, helpers, killers, and suppressors. Helpers educate the killers. Killers directly attack and eliminate the tumor cells. Suppressors hinder the immune response and promote cancer growth. Most immune-based therapies target the killers, however, there are many other components of the microenvironment in which cancer grows. In addition to the helpers and suppressors, the “soil” in which these cells thrive is important. We aim to understand how the “soil” (known as mesenchymal stem cells, MSCs) influences two key immune components in ovarian cancer patients, helper educational centers known as tertiary lymphoid structures (TLS) and suppressive T cells known as T regulatory cells (Tregs). Understanding this interplay is paramount to generating new and effective therapies for ovarian cancer patients, which is especially important in ovarian cancer because patients have not garnered the same therapeutic benefit with immune-based therapies as other solid tumors. In fact, only ~10% of ovarian cancer patients receive a survival benefit with immune-based therapies. Why is this? What is unique about ovarian cancer than allows it to effectively hide from the immune system?
In ovarian cancer, the balance of the immune response is often tipped to enhance the suppressors, thus killers cannot effectively target and kill the tumor cells. We aim to determine how to increase the “soil” (MSCs) that promotes helper TLS and prevents suppressive Tregs utilizing novel therapies. “Soil” cells which start in the bone marrow (BM-MSCs) can initiate the building of helper TLS. Thus, these BM-MSCs work with the immune system to increase anti-cancer immunity. “Soil” cells that develop within the ovarian cancer environment (CA-MSCs) can help enhance ovarian cancer growth by amplifying the suppressive function of Tregs. Thus, these local CA-MSCs work against the immune system to decrease anti-cancer immunity.
Altering the immune balance by targeting both the immune cells and the MSCs offers powerful new combinatorial treatment approaches. Our goal is to understand the specific factors within the ovarian cancer environment which impact this immune balance and to develop treatments to shift this balance to kill ovarian cancer. Specifically, we will study the steps necessary for BM-MSCs to support TLS formation and immune activation. We will also identify how local CA-MSCs recruit Tregs to decrease the immune response. We will specifically test if blocking the interaction between CA-MSCs and Tregs will shift the balance of immunity towards killing cancer.
This work can be quickly moved into clinical trials as the blocking drug we are testing (neuropilin-1; NRP1) is already in early clinical development and our team includes an ovarian cancer clinician and translational immunologist with experience writing, conducting and analyzing clinical trials. The vision of the Clinic and Laboratory Integration Program (CLIP) is to improve the effectiveness of cancer immunotherapies. This grant will meet this vision by developing a therapy that targets MSCs and the immune system for a synergistic effect on improved patient outcomes.
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