Investigating the Role of the Notch Pathway in HCC Immune Resistance

Amaia Lujambio Goizueta, PhD, an assistant professor of oncological sciences at the Icahn School of Medicine at Mount Sinai, discusses a new approach to overcoming resistance to immunotherapy for patients with hepatocellular carcinoma (HCC).

Lujambio Goizueta says that overexpression of the Notch receptor proteins may be linked to an oncogene in HCC that prevents cancer from being attacked by the immune system, and also makes the disease resistant to immunotherapy. Researchers are investigating the mechanism of the Notch oncogene in helping tumor cells avoid T cell regulation that would target them. Dysregulation of the Notch pathway is associated with cancer and other conditions.

In patients with HCC that is resistant to immune response, even T cells that reach tumor cells do not attack the cells, she says. Identifying the mechanism of resistance is necessary for immunotherapy to be effective.

According to Lujambio Goizueta, research is currently being done in mouse models to identify the resistance related to Notch signaling. If this research can be transferred to human cells, immunotherapies can be designed to overcome immune escape and induce T cell regulation of tumors.

TRANSCRIPTION:

0:08 | We have found that tumors that present genetic alteration, which is overexpression of Notch, which can be an oncogene in HCC—they are very good at hiding from the immune system. That makes the tumors with a Notch overexpression be resistant to immunotherapy. I keep coming and repeating the word in immunotherapy because this is one of the therapies that is most promising right now in HCC. So, we are trying to decipher the mechanism by which the Notch oncogene is inducing immune escape.

1:01 | So, we have found that there are the tumors that have a lower ability to attract T cells, which are cells of the immune system that can recognize specifically the tumor cells and basically kill them. There is a definitely a defect in the ability of those cells to recruit the immune T cells, but also, we are seeing that [even] those T cells that actually managed to get to the tumor, they are not able to kill the tumor cells.

If we are successful with our research, which is conducted mainly in mouse models, and we find a similar mechanism in [patients in] HCC, then that the therapies that we are testing in mice could be used in patients.