New study figures out which patients will react to immunotherapy

According to a new study, patients with head and neck cancer who have more chromosome 9 genetic material in their cancer cells survive three times longer after accepting immunotherapy than patients who have less of it. Chromosomes are the 23 superstructures that house, organize, and safeguard the DNA code in both healthy and cancerous cells.

The new study, which is being led by scientists from the UC San Diego Moores Cancer Center and NYU Grossman School of Medicine, focuses on the human immune system’s capacity to identify abnormal cancer cells and combat them.

By controlling checkpoint sensors, which prevent immune cells from attacking healthy cells, cancer cells conceal themselves from the system. Checkpoint inhibitors, a popular type of immunotherapy, use proteins called antibodies to restore tumor visibility.

However, according to the study’s authors, only 15% of patients with head and neck cancer benefit from immune checkpoint blockade. The condition known as “immune hot,” in which there are sufficient immune cells to detect antibodies, is necessary for them to function.

However, it is unclear why so many patients have insufficient immune cells close to their immune cold tumors. The study focuses on HPV-negative head and neck squamous-cell (HNSC-HPVneg) carcinomas, which are the most prevalent and deadly subtype of head and neck cancer, accounting for more than 200,000 fatalities annually worldwide.

The study, which was published online on November 14th, 2022 in the Proceedings of the National Academy of Sciences (PNAS), found that patients with HNSC-HPVneg cancer who had higher levels of a region on chromosome 9 called 9p24.1 in their cancer cells lived longer after receiving checkpoint inhibitor therapy—an average of 30 months—than those who had lower levels—living only 11 months on average.

These findings reveal 9p24.1 as a genetically defined axis that promises to determine for the first time whether HNSC patients will do well or poorly on a checkpoint inhibitor.

Teresa Davoli, PhD, Study Senior Author and Assistant Professor, Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, NYU Langone Health

She added, “If we had a way to tell which patients would not respond, physicians could be quickly switching them to chemotherapies instead of exposing them to the considerable side effects that come with immunotherapy.

Error-prone copying

Other types of changes could exacerbate the situation after initial genetic errors have turned healthy cells into cancer cells, the researchers claim. Changes in chromosome numbers are one of them, with some cancer cells having fewer than normal chromosomes and others having more.

When a cell divides into two and distributes its chromosomes equally among its daughter cells, which takes place billions of times as a single-celled human embryo multiplies to form a fetus, errors can occur. Copying errors can cause the number of chromosomes to double, disappear, or shorten from one cell generation to the next at every division.

According to the authors, the likelihood of copying errors is significantly higher during the heedless growth fueled by rapidly dividing cancer cells, which accounts for the significant chromosome copy number changes found in the majority of HPV-negative head and neck squamous-cell carcinomas.

The term “HPV-negative” refers to cancers of the head and neck that are not brought on by infection with the human papillomavirus (HPV). Instead, smoking, alcohol use, and chromosome copy aberrations are responsible for the much more prevalent HPV-negative cancers.

The chromosome arm 9p seems to be more likely to be lost in immune cold tumors that do not respond to immunotherapy, according to a 2021 study conducted by the same research group.

The region (locus) known as 9p21 is home to a large number of genes, including those that produce interferons, a family of immune system signaling proteins that can initiate an attack on cancer cells.

However, the earlier study did not pinpoint the region (or genes) on 9p that were in charge of “immune cold” checkpoint therapy resistance. According to the new research, the 9p24.1 locus rather than the 9p21 locus may hold the key.

The Cancer Genome Atlas, a large database on the genetics of cancer cells maintained by the National Cancer Institute, along with patient datasets from a company called Caris Life Sciences, were used to explore the degree of genomic loss of 9p24.1 in the cancer cells of patients with HNSC-HPVneg.

For the first time, the team connected 9p24.1 loss to the length of post-checkpoint inhibitor therapy survival. The extra copy of the 9p24.1 gene was also linked to immune cold characteristics in patients with other squamous cancer types, such as lung, cervical, and esophageal squamous cell carcinomas, the researchers discovered when they conducted whole exome analyses of 10 solid tumors.

Genes that control the synthesis and reaction to interferons, like JAK2, Janus kinases (Jak), which is located on 9p24.1, are known to be found in 9p chromosome sections. According to the team’s theory, extra 9p24.1 copies or amounts boost interferon response signaling in cancer cells through Jak signaling, which is known to entice more NK cells and T cells to infiltrate and attack tumor cells.

This finding justifies the development of 9p24.1 or Jak biomarker tests to select patients for checkpoint therapy. Jak DNA or RNA expression may need to be incorporated into precision treatment strategies for any squamous or solid tumor in which 9p24.1 dosage shapes the environment near tumors.

Xin Zhao, PhD, Study First Author and Postdoctoral Scholar, NYU Grossman School of Medicine, NYU Langone Health


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