A study led by researchers at NYU Grossman School of Medicine and UC San Diego Moores Cancer Center has found that patients with head and neck cancer who have more genetic material at a specific region on chromosome 9 in their cancer cells survive three times longer after receiving immune checkpoint therapy (ICT) than those with less genetic material at the same position. The results found patients with HPV-negative head and neck squamous-cell (HNSC-HPVneg) cancers who exhibited an increased dosage of a region on chromosome 9 called 9p24.1 in their cancer cells lived for 30 months on average after anti-PD-1 checkpoint inhibitor immunotherapy, while those with a lower 9p24.1 dosage survived for 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,” said Teresa Davoli, PhD, an assistant professor in the Institute for Systems Genetics at NYU Langone Health. “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.”
Davoli is co-senior author of the team’s published study in PNAS, which is titled, “Somatic 9p24.1 alterations in HPV– head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity.”
Cancer cells hide from the system by hijacking checkpoint sensors that keep the immune cells from attacking normal cells. Checkpoint inhibitor immunotherapy uses proteins called antibodies to make tumors visible again to the immune system. Anti-PD-1 immune checkpoint therapy is now an integral part of the standard of care in head and neck squamous cell cancer (HNSC), the authors noted. However, not all patients respond well to such therapy. “Despite remarkable deep and durable responses, the majority of patients do not benefit from anti-PD-1 therapy, even those whose tumors express high levels of PD-L1.”
Antibodies only work if there are enough immune cells present to notice them, a state known as an “immune hot,” tumor microenvironment (TME) but scientists understand little about why so many patients have too few immune cells near their “immune cold” tumors.
After initial genetic mistakes have transformed normal cells into cancer cells, other types of changes can worsen the situation, the researchers explained. Among these are changes in chromosome numbers, with some cancer cells containing more chromosomes than normal, and others less. Such somatic copy number alterations (SCNAs) happen because errors occur as a cell divides into two and splits its chromosomes equally among its daughter cells, which occurs billions of times as a single-celled human embryo multiplies to form a fetus. At each division, copying errors can lead to the doubling, loss of, or shortening of chromosomes from one generation of cells to the next.
For their newly reported study, the team investigated HPV-negative head and neck squamous-cell (HNSC-HPVneg) carcinomas, the most common and lethal subtype of head and neck cancer, with more than 200,000 deaths globally per year. Only about 15% of patients with head and neck cancer respond well to immune checkpoint blockade. Head and neck cancers have many causes, and HPV-negative refers to those not caused by infection with the human papillomavirus (HPV). The much more common HPV-negative cancers are instead caused by smoking, alcohol use, and chromosome copy aberrations. The likelihood of copying errors is much greater during the reckless growth driven by fast-dividing cancer cells, say the authors, which explains the “extensive” chromosome copy number changes present in most HPV-negative head and neck squamous cell carcinomas.
A 2021 study led by the investigators had shown that the 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 the locus 9p21. “Previously, we identified recurrent 9p21.3 loss as an early genetic driver of human papillomavirus-negative (HPV–) HNSC, associated with an immune-cold tumor microenvironment (TME) signal limited to HPV– disease,” the investigators explained. The earlier study, however, did not identify which region (and genes) were responsible for immune cold checkpoint therapy resistance. Commenting on their own, and other research, the team noted, “Despite these emerging 9p-related immune gene and ICT effects, attempts to dissect 9p have failed to reveal a clear candidate mediator, likely to be tissue specific, of immune response and ICT benefit.”
The newly reported work suggests that the 9p24.1 locus, more than a 9p21 locus, may be the key. For their analysis, the research team measured the extent of genomic loss of 9p24.1 in the cancer cells of patients with HNSC-HPVneg as captured by the National Cancer Institute’s massive database on cancer cell genetics, the Cancer Genome Atlas (TCGA), as well as in patient datasets from Caris Life Sciences. The team linked 9p24.1 loss for the first time to survival duration after checkpoint inhibitor therapy. “These data build on our previous report demonstrating that 9p somatic copy number loss in HPV– HNSC was associated with immune-cold tumor microenvironments and poor survival after anti-PD-1 immunotherapy,” they wrote.
When the researchers next carried out whole exome analyses of ten solid tumors, they also found that extra 9p24.1 led to immune cold features in patients with other squamous cancer types, including lung squamous cancers, cervical squamous cancer, and esophageal squamous cell carcinoma. “Importantly, not only did we confirm and extend binary 9p loss/immune-cold/ICT resistance observations in our and other recent reports, we demonstrated 9p24.1 gain as a possible driver of an immune activation and ICT response in HPV– HNSC and several other squamous cancers,” the scientists stated.
9p chromosome sections are known to include genes—such as JAK2 (Janus kinases; Jak) located on 9p24.1—that direct production of and response to interferons. In the team’s hypothesis, extra copies of 9p24.1 increase interferon response signaling 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 tests to select patients for checkpoint therapy,” said first study author Xin Zhao, PhD, a postdoctoral scholar in Davoli’s lab. “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.”
As the authors concluded, “…this report provides multiomic evidence from four cohorts that the spectrum of immune TME alterations from cold to hot in HPV– HNSC are highly influenced by somatic alterations in 9p24.1 dosage in HPV– HNSC … The strong associations between 9p24.1 gene dosage and immune TME [tumor microenvironment] open the opportunity for biomarker development to guide ICT in HPV– HNSC and other tumor types.”