Tiny, Yet Mighty: Neutrophils Could Fight Brain Cancer
Glioblastoma, the most common malignant form of brain cancer, spreads and progresses quickly. These tumors pop up anywhere glial cells can be found- which happens to be 90% of the brain; they spread and seep into other regions of brain, making surgery ineffective. Glioblastoma is also highly resistant to current chemotherapies and radiation therapies; even with persistence, every therapy is bound to also damage the patient as well. However, advances in our understanding of the tumor microenvironment could reveal a new path forward for this deadly disease. Where we used to understand tumors as homogenous, now we acknowledge that tumors are complex structures with different interactions between tumor cells and the cells around them, their tumoral microenvironment.
To address holes in the understanding of glioblastoma’s microenvironment, researchers at UCSF have focused on the implications of tumor associated neutrophils (TANs) on glioblastoma. Neutrophils are a particularly short-lived type of white blood cell. Within the bloodstream, their entire lifespans take place over the course of less than a day. Due to their transient nature, early studies suggested that TANs could have little to no impact on cancer despite neutrophils infiltrating many types of tumors . Now, TANs could be the next step in glioblastoma immunotherapy.
Investigating the lifespans of TANs, Lad et. al. performed an immunohistochemistry analysis on TANs and blood vessels in patient glioblasatomas. Neutrophils showed significant proximity to glioblastoma. Researchers saw that tumor-associated neutrophils closely bordered the thin lining of the brain. They found they were closer to this lining than certain types of glioblastoma stem cells that were already present. Researchers also studied the lifespan of neutrophils in tumor-conditioned media compared to non-conditioned media. In non-conditioned media, neutrophils exhibited no survival; however, in media containing secretome (proteins secreted by tumors), healthy neutrophils lasted as much as 90 hours. In patient tumors, the same neutrophil survival rates appeared again- demonstrating that patients with glioblastoma generate enough secreted proteins to trigger this effect.
When we contract any disease, antigen presenting cells break down the foreign substances into smaller pieces called antigens that our immune system can then recognize and activate against. When exposed to secretome, neutrophils process and present antigens; in particular, tumor associated neutrophils morph into antigens that enable the immune system to respond to glioblastoma in ways other types of neutrophils cannot.
In order to confirm this property, researchers tested the response of pulsed and unpulsed TAN to OVA peptide- a substance used to test immune responses- and cultured them with T cells. After 72 hours, T cells only proliferated with the pulsed TAN; implying that tumor associated neutrophils exhibit antigen presentation in response to tumor cells.
To test just how important neutrophils are to immune responses against tumors, they analyzed mice with neutrophils versus mice with a depleted number of neutrophils and tumor growth within each mouse population. Tumor growth was faster within mice with depleted TANs and grew around 7 times larger compared to mice with the usual amount of TANs. In order to reinforce the importance of interactions between TANs and T-cells, the researchers also compared mice with depleted T-cells and mice with normal T-cells in conjunction with the previous two categories. They found that the suppressive effect of TANs was absent without T-cells; in fact, mice with neutrophils and depleted T-cells experienced more growth than mice with both depleted neutrophils and T-cells, implying a possible pro-tumoral role of neutrophils. Through gene analysis, researchers found the reason why this occurs. Tumor suppression results from interactions between TANs and T-cells; however, when TANs in isolation tend to promote glioblastoma stem cells and amplify oncogenic signalling instead.
Ultimately, TANs represent a promising target for immunotherapy in glioblastoma. Spreading their influence from just lung cancer to brain cancers represents a future for TANs in the field of oncology as a whole- especially as researchers continue to clarify the ways in which the tumor microenvironment impacts the tumor itself.