Immune system contribution to tumor heterogeneity may influence liver cancer growth

By Sally Robertson, B.Sc.Jan 15 2020

Researchers at Mount Sinai School of Medicine say the immune system might contribute to the tumor heterogeneity seen in liver cancer that can affect the rate of cancer growth.

Image Credit: Sebastian Kaulitzki/Shutterstock.com

Liver tumors are often complex in their make-up, containing a highly diverse or “heterogenous” set of cells that can influence the rate at which cancer grows.

Mount Sinai researchers report that this heterogeneity, whether it is within the same tumor or between different regions of the same tumor nodule, occurs in about one-third of patients with hepatocellular cancer (HCC) - the most prevalent form of liver cancer - and that some of these tumors hijack various gene networks to aid their rapid growth.

The molecular heterogeneity of tumors presents a challenge to improving outcomes for liver cancer patients, since it contributes to drug resistance and tumor relapse following therapy. There is, therefore, an urgent need to understand the composition and function of tumor heterogeneity.

Mount Sinai researchers collaborated with other medical centers worldwide

To elucidate the mechanisms that promote tumor progression in individual patients, the team collaborated with other medical facilities around the world to conduct an integrated molecular analysis of gene expression, immune system activities, and DNA mutations from multiple different regions of the same tumor nodule among 14 liver cancer patients.

This is the first time that researchers have used single-cell RNA sequencing in multiple regions of the same tumor nodule, and the study is among the first to examine how the immune system contributes to the evolution of liver cancer.

Tumors are a complex ecosystem, and we're developing for the first time a blueprint of the different ways they can evolve in patients with liver cancer by interacting with the immune system,"

Augusto Villanueva, Assistant Professor in the Liver Cancer Program at The Tisch Cancer Institute at Mount Sinai.

"By better understanding how tumors progress, we're learning more about how they adapt to pharmacological pressures, and how they can develop mechanisms of resistance to cancer therapies. This greater awareness will hopefully lead to the identification of biomarkers that can predict which patients will be responsive to treatment."

Clinical implications associated with tumor heterogeneity

The researchers identified various clinical implications associated with the tumor heterogeneity, one of which was that a liver tumor can potentially be mischaracterized with the use of just a single biopsy. Although some tumors are homogeneous in their genetic makeup and immune cell infiltration, others are highly heterogeneous:

"This means that a biopsy from the same tumor could yield different information depending on where it was taken, and could thus affect clinical decision-making for the patient,” explains Villanueva.

Therefore the team’s efforts to learn how tumors evolve and the different trajectories they can take, is so important to future cancer research, as well as to effectively treating the disease, he adds.

Developments in liver cancer research

As immunotherapy approaches continue to revolutionize cancer research, one particularly promising area is liver cancer, the incidence of which is quickly increasing in the US and is now reaching 33,000 new cases annually.

Two-phase 2 clinical trials testing the effects of PD1 immune checkpoint inhibitors (which help the immune system recognize and target cancerous cells) have achieved such promising treatment responses that the FDA has granted accelerated approval status for the inhibitors as a second-line treatment for advanced HCC.

Furthermore, a more recent phase 3 clinical trial combining a PD-1 immune checkpoint inhibitor with an antiangiogenic, improved patient survival more than the current first-line standard of care.

"Our work is particularly relevant”

However, only an estimated one-third of patients with HCC are thought to have a favorable treatment response to this type of treatment, which is not an uncommon outcome when immunotherapies are used.

"The immune system imposes significant constraints on liver cancer evolution, and by investigating the interaction of immune cells and cancer cells at the molecular level we're trying to predict or anticipate mechanisms of tumor resistance," explains lead author Bojan Losic.

"Our work is particularly relevant considering the remarkable success of immune checkpoint inhibitors in some heterogeneous solid tumors."