Uncovering How the Immune System Sculpts Cancer

Elizabeth Borden, PhD, an MD/PhD student at the University of Arizona College of Medicine – Phoenix, has been examining how the immune system impacts the neoantigen landscape in human tumors. Her findings — exploring that concept — were recently published by Immunity, a Cell Press publication.

Under the guidance of Karen T. Hastings, MD, PhD, inaugural chair of the U of A College of Medicine – Phoenix’s Department of Dermatology, Dr. Borden and a team of researchers investigated the process by which the immune system shapes emerging cancers.

Immunoediting is the concept that the immune system sculpts the tumor that arises in a patient by killing cancer cells that are visible to the immune system. This concept has been showcased in models, but there was little direct evidence for it occurring in human cancers.

“Prior data consistent with immunoediting in human cancers is associative,” Dr. Hastings said. “We sought to conclusively demonstrate the effects of the immune system on sculpting the neoantigen landscape in untreated human tumors.”

To uncover this mystery, Dr. Borden and a collaborative team of researchers led by Dr. Hastings sought the unique approach of comparing tumors from healthy patients to tumors from patients with a suppressed immune system. 

“We looked at the differences in the tumors that arose in those two populations of patients,” Dr. Borden said. “We showed evidence that there was immunoediting that occurred in the tumors from patients with an intact immune system compared to tumors from patients who were on medications that suppressed the immune system for another clinical indication, and then we showed how that immunoediting took place."

Neoantigens are little pieces of mutated proteins from cells that are displayed on the cell surface. They allow the body to distinguish cells that are cancerous from those that are not.

Essentially, when mutations occur in cancer, Dr. Borden said they result in peptides that are displayed on the cell surface permitting the immune system to recognize that the cell is not normal tissue, allowing for an immune response.

The team took advantage of a clinical feature of cutaneous squamous cell carcinoma. Cutaneous squamous cell carcinoma has a dramatically increased incidence in immunosuppressed individuals. According to Dr. Hastings, the comparison between tumors from the two populations of patients gave the team the opportunity to demonstrate the changes in the neoantigen landscape in human tumors that are due to the immune system.

Overall, the study provided evidence that the immune system shapes the neoantigen profile in human tumors by restricting the neoantigens that elicit a strong immune response to a small proportion of the cancer cells. 

For Dr. Borden, understanding how the immune system shapes the tumor neoantigen landscape, or how a tumor escapes the immune system, is the first step to creating therapies. For example, tumors that have fewer immune cells within the tumor, even though the immune system is intact, or tumors from immunosuppressed individuals have a larger number of strong neoantigens expressed in all cancer cells. Effectively targeting these neoantigens will likely require a combination of therapies to boost the immune response. 

Dr. Hastings supported this notion. She noted that this study provides the strongest data so far to support immunoediting in human cancer and identifies the predominant effects of immunoediting on the neoantigen landscape.

“We seek to further understand the mechanisms of immunoediting throughout cancer development and to apply this knowledge to improve cancer prevention strategies and to personalize cancer treatment,” Dr. Hastings said.

Dr. Borden hopes the next studies will involve examining a single tumor over time and determining the cellular mechanisms that give rise to restricting the strongest neoantigens to a small portion of the tumor. 

“The goal is to impact therapeutics,” Dr. Borden said. “Applying the principles learned in this study to the design of clinical trials for neoantigen targeted cancer vaccines would be valuable.”