Despite real advances in immune-checkpoint therapy for the treatment of patients diagnosed with human papillomavirus–negative head and neck squamous cancer, drug resistance remains prevalent, is poorly understood, and is generally unidentified by existing biomarker tests.

Worldwide, head and neck accounts for approximately 900,000 cases and over 400,000 deaths annually. [1] And while this disease has multiple causes, the human papillomavirus (HPV), a sexually transmitted infection, is the most common and lethal subtype are HPV-negative head and neck cancers. In the United States, this subtype accounts for 3% of all malignancies, with approximately 66,000 cases annually, resulting in 15,000 deaths annually. [2]

A new study, funded in part by the Instituto Cura, Cancer Research UK, Mark Foundation for Cancer Research, the National Institutes of Health (NIH), and others, helps researchers to better understand the association between the most lethal form of head and neck cancer linked to chromosomal alterations of HPV.[3]

“Typically, head and neck cancers begin in the squamous cells that line the mucosal surfaces, such as inside the mouth and throat and there are multiple treatment options, including surgery, radiation, and chemotherapy,” noted Ezra Cohen, MD, co-director of the Gleiberman Head and Neck Cancer Center at Moores Cancer Center at UC San Diego Health.

“But these cancers are complex and no single treatment works for every patient every time, which is why immune checkpoint inhibitors were developed, which use antibodies to make tumor cells visible to a patient’s immune system.”

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Immune checkpoint therapy first emerged in the 1990s and has progressed dramatically in recent years, but drug resistance in head and neck cancer cases remains prevalent, poorly understood, and largely unidentified by current biomarker tests, said Cohen.

The available PD-1 immune checkpoint antibody therapy produces durable responses in 15% of patients with head and neck squamous cancer. The remaining 85% receive no benefit and may, in fact, experience severe, immune-related adverse effects.

Risk factors
Like other types of head and neck cancer, the HPV-negative subtype has multiple risk factors, such as tobacco and alcohol consumption, human papillomavirus (HPV) infection (for oropharyngeal cancer), and Epstein-Barr virus (EBV) infection (for nasopharyngeal cancer). But the primary cause appears to be genetic copy-number alterations.

In the new study, published in the November 14, 2022 issue of PNAS, Cohen, with colleagues at Moores Cancer Center, UC San Diego School of Medicine, and elsewhere, expand and deepen understanding of how genetic aberrations fuel HPV-negative head and neck cancers and, potentially, provide paths to further refinement and improvement of immune checkpoint inhibitors for HPV-negative head and neck cancers.[3]

In research published, last year in PNAS (Proceedings of the National Academy of Science) the same team of scientists laid the groundwork, becoming the first to discover the impact of the loss of a copy of a genetic region on the short p-arm of chromosome 9 in causing immune escape and Immune checkpoint therapy resistance of HPV-negative head and neck cancer. [4]

New questions
But the 2021 findings raised new questions about whether the genetic abnormalities might involve losses at more than one locus on chromosome 9p. The new work provides answers, based on multi-omic immunogenetic evidence from analyses of each band at each locus, and each gene within each band in four different patient cohorts.

“We found that it’s not just the 9p21 locus on chromosome 9p that’s involved, but also the 9p24 locus, which may be even more important in driving resistance to immune checkpoint therapy; and surprisingly we found that gains of these genetic regions, at least in the case of HPV-negative head and neck squamous cancer, were associated with Immune checkpoint therapy survival benefit,” noted study co-senior author and co-corresponding author Scott Lippman, MD,  Distinguished Chugai Professor and Moores Cancer Center director.

An increased median survival rate
The researchers found that median survival rates were three-fold higher when treating 9p-gain cases, specific tumors with 9p24.1 band expression above the 60th percentile compared to chemotherapy (but lower below the transcript threshold.) Whole-exome analyses of ten solid tumors suggested that these 9p-related Immune checkpoint therapy findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-response associations exist.

These 9p24.1-alteration/immune-oncology findings reveal genetically defined Immune checkpoint therapy sensitivity and -resistance in HPV-negative squamous tumors, addressing a major unmet medical need for precision therapy for these patients. They identify likely ICT responses and resistance mechanisms that point toward treatment options more likely to be effective.

“This discovery may have a profound impact in the science and practice of immune-oncology,” said Lippman, revealing the basis and model of recurrent chromosomal alterations as oncogenic drivers, and key determinants of immune phenotype, and identifying a novel Immune checkpoint therapy-resistance mechanism leading to a new standard-of-care diagnostic biomarker test.

“This work is progressively defining the genetic basis for responsiveness to one of the most employed forms of oncology therapeutics,” added co-author Webster K. Cavenee, Ph.D., Distinguished Professor Emeritus at UC San Diego School of Medicine.

“The ability to identify these distinct groups of patients can be expected to have a significant clinical impact for them,” Cavenee concluded.

[1] Global Cancer Observatory. International Agency for Research on Cancer. World Health Organization. Online. Last accessed on November 16, 2022.
[2] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12. PMID: 35020204.
[3] Zhao X, Cohen EEW, William WN Jr, Bianchi JJ, Abraham JP, Magee D, Spetzler DB, Gutkind JS, Alexandrov LB, Cavenee WK, Lippman SM, Davoli T. Somatic 9p24.1 alterations in HPV head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity. Proc Natl Acad Sci U S A. 2022 Nov 22;119(47):e2213835119. doi: 10.1073/pnas.2213835119. Epub 2022 Nov 17. PMID: 36395141.
[4] William WN Jr, Zhao X, Bianchi JJ, Lin HY, Cheng P, Lee JJ, Carter H, Alexandrov LB, Abraham JP, Spetzler DB, Dubinett SM, Cleveland DW, Cavenee W, Davoli T, Lippman SM. Immune evasion in HPV head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss. Proc Natl Acad Sci U S A. 2021 May 11;118(19):e2022655118. doi: 10.1073/pnas.2022655118. PMID: 33952700; PMCID: PMC8126856.

Featured image by Loume Visser on Unsplash. Used with permission.

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