One of the reasons why cancer continues developing and growing is not just because cancer cells exist, but because they can recruit help from the body’s own blood vessels, stromal cells, and immune cells.
Fusion-driven non-small cell lung cancers (NSCLC) initially develop because of oncogenes, an altered form of a gene involved in normal cell growth. A common treatment for fusion-driven NSCLC are targeted therapies, also known as tyrosine kinase inhibitors (TKI) that block the effect of oncogenes, but tumors commonly become resistant and the cancers recur.
University of Colorado Cancer Center member Erin Schenk, MD, PhD, an assistant professor of medical oncology, is researching new ideas about why that resistance develops and how these cancers could be treated by targeting innate immunity. She recently received a three-year LUNGevity Career Development Award, given by the LUNGevity Foundation to support critical lung cancer research.
“I’m really excited to have the support to keep working on these questions,” Schenk says. “We’re really working to understand how and why this resistance develops.”
Understanding how cells communicate
Schenk’s research focuses on how innate immune cells interact with cancer cells. The innate immune system is the body’s first line of defense against abnormal cells, and through her research Schenk has found that in many oncogene-driven lung cancers, innate immune cells interface with cancer cells.
“We’re trying to understand how these innate immune cells interact with cancer cells,” Schenk explains. “Basically, we’re seeing that innate immune cells are sending care packages to cancer cells, releasing factors that are favorable to cancer cell growth.”
When that interface between the two cells types happens, cancer cells are not as responsive to TKI therapies, she says. TKIs are the preferred first-line treatment for patients with most fusion-driven NSCLC because of their usual level of effectiveness and fewer side effects when compared to other treatments like chemotherapy. T cell-targeting immunotherapies, which are widely available in clinical practice, have not significantly helped patients with fusion-driven NSCLC. Schenk believes her findings suggest a different type of immunotherapy may benefit these patients.
“One of the first hurdles is conceptually helping people to understand that the immune system is important in these specific types of lung cancer,” Schenk says. “Clinically, the immunotherapies we have do not work well for patients with fusion-driven NSCLC. In my laboratory, we’re looking at a new way of thinking about the immune system and fusion-driven NSCLC and hopefully identifying new targets for these patients.”
Through the support of LUNGevity, Schenk’s laboratory is focused on combining therapies that deplete broad populations of innate immune cells with TKIs for fusion-driven NSCLC. These initial experiments will help establish the role of innate immune cells in TKI response. “There’s a huge diversity in these types of immune cells and we’re excited to tease out which is the key player so treatment approaches that are more specific to that cell type can be considered,” she says.
Helping patients do better for longer
Working with tissue samples donated by patients with lung cancer, many of whom have received treatment at the CU Cancer Center, Schenk is working to identify not only the types of cells present, but also using bioinformatic approaches to study where the cells are positioned, and whether there is a significant interface between the cell membranes. In other words, whether the cancer cells and innate immune cells are “touching,” which suggests they may be actively communicating with one another.
Understanding how and where this communication is happening may lead to developing more targeted therapies to eliminate these pro-tumor innate immune cells. Ultimately, the hope is that by removing these innate immune cells, other components of the immune system have easier access to identify and eliminate the cancer cells.
“I think the benefit will be one, recognizing a new target in these patients to develop better therapeutics and two, working toward eliminating these innate immune cells that are helping the cancer and clearing the way for T cells to come in,” Schenk says. “If we can have either more tumor shrinkage with the first TKI treatment, or if we can find a way to reboot the TKI response that was lost by targeting innate immune cells, there’s a potential for patients to do better for longer.”