Making Cold Tumors Hot: Blake Heath
Human papilloma virus (HPV) is associated with the development of a variety of cancers, but for the general public, HPV may be best known in the context of vaccines and their role in preventing cervical cancer. There is, however, a growing recognition around HPV’s close association with the development of head and neck cancer, which is highlighted by statistics that show the incidence rate of HPV-associated head and neck cancer exceeding the rate of HPV-associated cervical cancer.
While infection with HPV may have multiple contributions to the development of cancer, one particularly interesting aspect of HPV infection is its impact on the immune system. HPV-associated tumor cells, like cancers in general, have the ability to evade the immune system, preventing immune cells from targeting and killing the nascent malignancies.
This is especially important because the effectiveness of current cancer therapies is limited in solid tumor cancers like head and neck squamous cell carcinoma (HNSCC). Many common cancer therapies, like radiation and surgery, can have complications or cause collateral damage, which has led researchers to focus on using immunotherapies to harness the immune system to better target and fight the cancer.
But these immunotherapies also have their limitations. Their effectiveness relies on the ability of the immune cells to find and localize in the tumor environment. This is a challenge in HNSCC because many of these tumors are considered “cold,” meaning that they have ways to avoid triggering the immune system’s inflammatory – or “hot” – response. This “hot” response is needed in order for the body to mount the necessary anti-cancer immune response. So, if these tumors are “cold” and hidden from the immune cells, immunotherapies have limited impact because no “hot” response can be mustered. So, understanding the underlying biology of how cancer cells stay “cold” and hide from the immune system could help us identify new ways to target and treat tumors and improve the impact of current immunotherapies.
Blake Heath
This is the goal of Blake Heath, a PhD student in the Graduate Program in Immunology at the University of Michigan. Blake is a member of Yu Leo Lei’s lab, which studies head and neck cancer with the ultimate goal of using immunotherapy and other immune response-modulating techniques to combat cancer.
In his current project, Blake studies type I interferons (IFN-I) and how they could be used to fight tumors. IFN-Is are a class of proteins that, when secreted, help regulate the activity of the immune system, playing key roles in the response to virus infections. In the context of cancer, IFN-Is are considered to be anti-tumor because they lead to the activation of immune cells that can move to the tumor and kill the cancer cells.
Blake wants to understand the mechanism of how these type I IFNs are regulated so that they can be harnessed to fight cancer. In most cases, the tumor microenvironment has low levels of IFN-I signaling because cancers often have mechanisms to suppress their expression, which in turn keeps them “cold” and contributes to their evasion of the immune system. By understanding how cancer cells suppress IFN-Is, Blake hopes to identify ways to target the repressive mechanism to ramp up IFN-I production and make the tumor “hot” to help the body’s immune cells find and fight the cancer.
Blake’s work builds on the findings from other members of the Lei Lab, which has worked on identifying and characterizing the regulators of IFN-I production. One of the major focuses of the lab is to understand the signaling machinery around an intracellular protein called STING, or Stimulator of Interferon Genes. As its name would suggest, this protein acts as a major hub for the various signaling processes that lead to IFN-I production. One illustrative example of STING’s connection to IFN-I production can be found in its relationship with another intracellular protein known as cGAS. This protein acts as a molecular sensor on the lookout for free-floating double stranded nucleic acid (i.e. DNA), a signal that the cell uses as a danger alert that indicates the likely presence of a pathogen like a virus. If this free-floating foreign DNA is present, it can be detected by cGAS, which binds to the DNA. Once bound, this activates a signaling cascade to activate STING, resulting in the production of type I IFNs.
But this response mechanism is only helpful if it works properly, and viruses like HPV have developed ways to break the system. HPV infection leads to the production of viral proteins that act as oncogenes to induce cancer development. The Lei lab found that some of these proteins can induce the destruction of STING. Without this key signaling hub, the cell’s ability to mount a normal IFN-I response is undermined. And by hampering the STING-mediated IFN-I response, the HPV-positive cancer cells can keep themselves “cold” and more easily evade the immune system.
Due to the key role of STING in producing an IFN-I response, researchers have worked to identify and develop ways to reverse the impact of both HPV-positive and HPV-negative immune inhibition in these “cold” tumors. These researchers, like Blake, hope to restore the IFN-I response and make the “cold” tumors “hot,” recruiting the body’s immune cells to fight the cancer. This idea may hold promise as several approaches for activating STING have entered into clinical trials.
STING, it turns out, can be regulated by a variety of factors in addition to HPV viral proteins. Blake is currently investigating other mechanisms that cancer cells use to inhibit IFN-I production, and one recent finding may have identified another key protein. Blake’s work indicates that a class of proteins, which are typically associated with innate immune signaling and the detection of pathogens, plays a key role in regulating type I IFN signaling in the context of HNSCC. These proteins are known to have a diverse set of roles within the cell but are generally thought of as receptors that act as pathogen sensors and can, among a variety of functions, trigger inflammatory and cell death signaling cascades. Blake found that certain members of this protein family can inhibit STING signaling in the context of HNSCC, highlighting another mechanism that tumor cells can use to limit IFN-I signaling to stay “cold.” Importantly, Blake found that inhibition of this protein restored STING’s function and activated its downstream signaling cascades to produce IFN-Is.
Blake is currently working to understand how this inhibition impacts tumor size and development, and these encouraging findings suggest that he has identified a novel mechanism that could be targeted in cancers to turn “cold” tumors “hot” and expose the tumor cells to the body’s anti-cancer immune response. Such an approach could complement and improve upon the efficacy of immunotherapies currently on the market and improve the outcomes for cancer patients.
Special thanks to:
Blake Heath, PhD graduate student, Lei Lab, University of Michigan (heathbr@umich.edu)