New discovery shows which patients will survive longer after immunotherapy

New discovery shows which patients will survive longer after immunotherapy

Head and neck cancer patients who have more genetic material on chromosome 9 in their cancer cells survive three times longer after immunotherapy than patients with less genetic material, a new study finds. In both 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 centers on the human immune system's ability to 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 the leading class of immunotherapy, checkpoint inhibitors use proteins called antibodies to make tumors visible again.

However, in head and neck cancer, only about 15 percent of patients respond well to immune checkpoint blockade, say the study authors. Antibodies only work when there are enough immune cells to notice them, a condition called “immune hot,” although the field understands little about why so many patients have too few immune cells near their immune cold tumors. Specifically, the study looks at HPV-negative head and neck squamous cell carcinoma (HNSC-HPVneg), the most common and deadliest subtype of head and neck cancer with more than 200,000 deaths worldwide per year.

The study, published online the week of November 14 in the Proceedings of the National Academy of Sciences (PNAS), found that patients with HNSC-HPVneg cancers with a greater supply in their cancer cells of a region on chromosome 9 called 9p24.1 live 30 months on average after treatment with checkpoint inhibitors, while those with smaller amounts of them on average Survive 11 months.

These results show that 9p24.1 is a genetically defined axis that promises to determine for the first time whether HNSC patients do well or poorly with a checkpoint inhibitor.

If we could determine which patients would not respond, doctors could quickly switch them to chemotherapy instead of subjecting them to the significant side effects of immunotherapy.”

Teresa Davoli, PhD, co-senior study author, member of the Institute for Systems Genetics at NYU Langone Health

Error-prone copying

After initial genetic errors turn normal cells into cancer cells, other types of changes can make the situation worse, the researchers say. These include changes in the number of chromosomes, with some cancer cells containing more chromosomes than normal and others containing fewer. Such copy number changes occur because errors occur when a cell divides in two and distributes its chromosomes evenly among its daughter cells, which occurs billions of times when a single-celled human embryo reproduces to form a fetus. With each division, copying errors can result in the duplication, loss, or shortening of chromosomes from one cell generation 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 chromosome copy number changes present in most HPV-negative head and neck squamous cell carcinomas. Head and neck cancer has many causes, and HPV negative refers to those not caused by human papillomavirus (HPV) infection. The much more common HPV-negative cancers are instead caused by smoking, alcohol consumption and chromosomal aberrations.

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A 2021 study led by the same research team had shown that chromosome arm 9p is more likely to be lost in immune cold tumors that do not respond to immunotherapy. 9p houses many genes, including those that encode interferons, a set of immune system signaling proteins that can trigger an attack on cancer cells, at a location called 9p21. However, the previous study did not identify which region (and which genes) on 9p were responsible for resistance to the “immune cold” checkpoint therapy. The new work suggests that the 9p24.1 locus, more than a 9p21 locus, may be key.

For the current analysis, the research team measured the extent of genomic loss of 9p24.1 in the cancer cells of patients with HNSC-HPVneg, as recorded in the National Cancer Institute's extensive database of cancer cell genetics, the Cancer Genome Atlas, in patient records from a company called Caris Life Sciences. The team linked 9p24.1 loss to survival after checkpoint inhibitor therapy for the first time. When the researchers next conducted a whole exome analysis of 10 solid tumors, they also found that additional 9p24.1 resulted in immune cold features in patients with other squamous cell carcinomas, including lung squamous cell carcinoma, cervical squamous cell carcinoma, and esophageal squamous cell carcinoma.

9p chromosome segments are known to contain genes - such as JAK2, Janus kinases (Jak), located on 9p24.1 - that control production and response to interferons. In the team's hypothesis, additional copies or amounts of 9p24.1 increase interferon response signals in cancer cells through Jak signaling, which is known to recruit more NK cells and T cells to invade and attack tumor cells.

“This finding justifies the development of 9p24.1 or Jak biomarker assays to select patients for checkpoint therapy,” says study lead author Xin Zhao, PhD, a postdoctoral researcher in Dr. Davoli. “Jak DNA or RNA expression may need to be integrated into precision treatment strategies for any squamous or solid tumor where 9p24.1 dosage shapes the environment near tumors.”

Together with Dr. Davoli and Dr. Zhao was Dr. Joy Bianchi study author at the Institute for Systems Genetics at NYU Langone Health. Also authors of the study were co-senior author Scott Lippman and Ezra Cohen of UC San Diego 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 of Caris Life Sciences, Texas.

Funding for this research came from 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, P50 CA097007 and P30 CA023100). ), an MRA Young Investigator Award, the Packard Fellowship for Science and Engineering, the National Foundation for Cancer Research, and the Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Dream Team Translational Cancer Research (Grant SU2C-AACR-DT-25-17 ).

Source:

NYU Langone

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