PNAS: Newly discovered cancer cell biology indicates which patients respond to immunotherapy

A new study found that patients with head and neck cancer who received immunotherapy had more genetic material on chromosome 9 in their cancer cells survived three times
longer than those with less genetic material on chromosome 9.
In normal and cancer cells, chromosomes are 23 superstructures that house, organize, and protect DNA code
.

The new study, led by researchers at New York University's Grossman School of Medicine and the University of California, San Diego Moores Cancer Center, revolves around the human immune system, which can recognize abnormal cancer cells and attack them
.
Cancer cells evade the system
by hijacking "checkpoint" sensors that prevent immune cells from attacking normal cells.
Checkpoint inhibitors are a leading immunotherapy that uses a protein called antibodies to make tumors "visible"
again.

However, for head and neck cancer, only about 15 percent of patients respond well
to immune checkpoint blockades, the study's authors said.
Antibodies only work if enough immune cells notice them, a state known as "immune fever," a field that knows so little about why immune cells near immunocold tumors in so
many patients are too little.
The study specifically focused on HPV-negative squamous cell carcinoma of the head and neck (HNSC-HPVneg), the most common and deadliest subtype of head and neck cancer that kills more than 200,000 people worldwide each year
.

The study was published online Nov.
14 in
the Proceedings of the National Academy of Sciences (PNAS).
The study found that patients with HNSC-HPVneg cancer with a higher supply of cancer cells in the 9p24.
1 region of chromosome 9 survived an average of 30 months after treatment with checkpoint inhibitors, while patients with lower levels of checkpoint inhibitors survived an average of 11 months
.

"These findings reveal that 9p24.
1 is a genetically defined axis that holds promise for the first time determining whether nasopharyngeal carcinoma patients perform well or badly with checkpoint inhibitors," said
Teresa Davoli, Ph.
D.
, assistant professor at the Institute of Systems Genetics at NYU Langone School of Health, and senior study co-author.

"If we have a way to know which patients are not responding, doctors can quickly switch them to chemotherapy instead of exposing them to
the huge side effects that come with immunotherapy.
"

Error-prone replication

Other types of changes may make the situation worse after an initial genetic error turns normal cells into cancer cells, the
researchers say.
These include changes in the number of chromosomes, with some cancer cells containing more chromosomes than normal cells, while others have less
.
This copy number change occurs because errors occur when one cell divides into two and divides its chromosomes evenly in daughter cells, a condition that occurs billions of times
when single-celled human embryos proliferate to form fetuses.
In each division, replication errors can result in the doubling, loss, or shortening of chromosomes from one cell to the next

The authors say that replication errors are much more likely during reckless growth driven by rapidly dividing cancer cells, which explains the "extensive" chromosomal copy number changes
that occur in most HPV-negative squamous cell carcinomas of the head and neck.
There are many causes of head and neck cancer, and HPV-negative refers to those cancers that are not caused by infection with human papillomavirus (HPV
).
The more common HPV-negative cancers are caused
by smoking, alcohol consumption, and chromosomal replication aberrations.

A study led by the research team in 2021 showed that chromosome arm 9p is more likely to be lost in immunocold tumors that do not respond to
immunotherapy.
9p contains many genes, including those encoding interferon, a group of immune system signaling proteins that trigger an attack on cancer cells at a location (site) called 9p21
.
However, earlier studies did not determine which region (and gene) on 9p was responsible for "immune cold" checkpoint treatment for drug resistance
.
The new study suggests that the 9p24.
1 locus may be the key, rather than the 9p21 locus
.

In the current analysis, the team measured the extent of 9p24.
1 genome loss in cancer cells in HNSC-HPVneg patients, from the Cancer Genome Atlas, the National Cancer Institute's large-scale database on cancer cell genetics, and the patient dataset
from Caris Life Sciences.
For the first time, the team linked
9p24.
1 deletion to survival after checkpoint inhibitor treatment.
When the researchers next performed a "whole exome" analysis of 10 solid tumors, they also found that an extra 9p24.
1 gene caused immunocold signatures in patients with other squamous cell carcinoma types, including lung cancer, squamous cell carcinoma, cervical cancer, and esophageal cancer
.

The known 9p chromosome fraction includes genes such as JAK2-Janus kinase (Jak), located on 9p24.
1, which direct the production and response
of interferon.
In the team's hypothesis, the extra 9p24.
1 copy, or quantity, increased interferon response signaling in cancer cells via Jak signaling, which is known to recruit more NK cells and T cells to invade and attack tumor cells
.

"This finding informs the development of 9p24.
1 or Jak biomarker tests to select patients for checkpoint therapy," said
Xin Zhao, PhD, a postdoctoral scholar in Davoli's lab and first study author.
"Jak DNA or RNA expression may need to incorporate precision treatment strategies for any squamous or solid tumor, where the 9p24.
1 dose shapes the environment
near the tumor.
"

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