Head and neck cancer patients who have more genetic material on chromosome 9 in their cancer cells survive three times longer after receiving immunotherapy than those who have less genetic material there, according to a new study. Inside normal and cancer cells, chromosomes are the 23 superstructures that house, organize, and protect the DNA code.
Led by researchers at NYU Grossman School of Medicine and UC San Diego Moores Cancer Center, the new study revolves around the human immune system, which can recognize cancer cells as abnormal and attack them. Cancer cells hide from the system by hijacking checkpoint sensors that prevent immune cells from attacking normal cells. As a leading class of immunotherapy, checkpoint inhibitors use proteins called antibodies to make tumors visible again.
However, for head and neck cancer, only about 15 percent of patients respond well to immune checkpoint blockade, the study authors say. The antibodies only work if enough immune cells are present to notice them, a state called “immune hot,” with the field understanding little about why so many patients have too few immune cells near their immune-cold tumors. . Specifically, the study addresses HPV-negative head and neck squamous cell carcinomas (HNSC-HPVneg), the most common and lethal subtype of head and neck cancer with more than 200,000 deaths worldwide each year .
Published online the week of November 14 in the Proceedings of the National Academy of Sciences (PNAS), the study found that HNSC-HPVneg cancer patients with an increased supply of their cancer cells from a region of chromosome 9 called 9p24.1 lives an average of 30 months after treatment with checkpoint inhibitors, while those with lower amounts survive for an average of 11 months.
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 with a checkpoint inhibitor.
If we had a way of knowing which patients would not respond, doctors could quickly switch them to chemotherapy instead of exposing them to the considerable side effects that come with immunotherapy.”
Study co-author Teresa Davoli, PhD, a member of the Systems Genetics Institute at NYU Langone Health
Error prone copy
After the initial genetic mistakes have transformed normal cells into cancer cells, other kinds of changes can make things worse, researchers say. Among these are changes in the number of chromosomes, with some cancer cells containing more chromosomes than normal and others fewer. These copy number changes occur because errors occur when a cell divides in two and divides its chromosomes equally among its daughter cells, which happens billions of times when an embryo single-celled human multiplies to form a fetus. At each division, copying errors can cause chromosomes to be duplicated, lost, or shortened from one generation of cells to the next.
The likelihood of copying errors is much greater during the reckless growth driven by rapidly dividing cancer cells, the authors say, which explains the extensive changes in chromosomal copy number present in most squamous cell carcinomas. Head and neck squamous cells negative for HPV. Head and neck cancers have many causes, and HPV-negative cancers refer to those that are not caused by human papillomavirus (HPV) infection. HPV-negative cancers, which are much more common, are caused by smoking, alcohol consumption, and chromosomal copy aberrations.
A 2021 study led by the same research team had shown that the arm of chromosome 9p is more likely to be lost in immune cold tumors that do not respond to immunotherapy. 9p houses many genes, including those that code for interferons, a set of immune system signaling proteins that can trigger an attack on cancer cells, at a location (locus) called 9p21. The previous study, however, did not identify which region (and genes) on 9p were responsible for resistance to the “immune cold” checkpoint therapy. The new work suggests that the 9p24.1 locus, rather than a 9p21 locus, may be the key.
For the current analysis, the research team measured the extent of genomic loss of 9p24.1 in cancer cells from HNSC-HPVneg patients as captured by the massive database of the National Cancer Institute on cancer cell genetics, the Cancer Genome Atlas, as well as patient data sets from a company called Caris Life Sciences. The team linked the loss of 9p24.1 for the first time with the length of survival after checkpoint inhibitor therapy. When the researchers did a whole-exome analysis of 10 solid tumors, they also found that the extra 9p24.1 led to immune cold features in patients with other types of squamous cancer, including squamous lung cancers, cervical squamous cancer and squamous cell carcinoma of the esophagus.
Chromosome sections 9p are known to include genes, such as JAK2, Janus kinases (Jak), located at 9p24.1, which direct the production and response to interferons. According to the team’s hypothesis, the extra copies or amounts of 9p24.1 increase the signaling of the interferon response in cancer cells through Jak signaling, which is known to recruit more NK cells and cells. T cells to invade and attack tumor cells.
“This finding justifies the development of 9p24.1 or Jak biomarker tests to select patients for control therapy,” says first study author Xin Zhao, PhD, a postdoctoral scholar in Dr. Come on “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 tumor-proximal environment” .
Together with Dr. Davoli and Dr. Zhao, an author of the study at the Institute of Systems Genetics at NYU Langone Health was Dr. Joy Bianchi. Also co-authoring the study were co-senior author Scott Lippman and Ezra Cohen of UC San Diego’s Moores Cancer Center; J. Silvio Gutkind and Ludmil Alexandrov at UC San Diego; William William Jr. at the University of Texas and Hospital BP, Brazil; and Jim Abraham, Daniel Magee and David Spetzler at Caris Life Sciences, Texas.
Funding for this research came from the Instituto Cura, Cancer Research UK Grand Challenge, Mark Foundation for Cancer Research (C5470/A27144), the National Institutes of Health (grants R00 CA212621, R37 CA248631, R01DE026644, P01 CA106451, P500 CA0300 , P500 CA0300, and P5300 CA0300). ), an MRA Young Investigator Award, the Packard Fellowship for Science and Engineering, the National Foundation for Cancer Research, and Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Dream Team Translational Cancer Research (grant SU2C-AACR-DT-25-17) . ).