Head and neck cancers usually begin in the squamous cells at the edge of the mucosal surfaces in the head and neck. These cancers are generally referred to as Head and Neck Squamous Cell Carcinomas (HNSCCs).
Head and neck cancers can also begin in the salivary glands, muscles or nerves of the head and neck, but they are much less common than HNSCC which make up for 90% of the total head and neck cancers.
HNSCC can form in the squamous cell layers of the oral cavity, larynx, nasopharynx and oropharynx, from where is able to invade and ultimately form metastasis.
It is the 8th most common cancer worldwide and its incidence is expected to increase of 52% by 2045. People affected by this type of tumor have an average 5-year mortality rate of 50%, and survivors display the 2nd highest suicide rate among all cancers.
It is especially common in Asia and Europe, and in general men have an higher risk to develop HNSCC compared to women.
Exposure to risk factors is often not enough for HNSCC oncogenesis. There must be a concomitance of different events to cause HNSCC, and multiple genetic alterations for the tumor to become invasive.
The contact with carcinogens causes the activation of the carcinogen metabolism. This can lead to proper detoxification and extraction from cells and thus a healthy individual, or to DNA damage. DNA damage can either be successfully repaired and maintain the person healthy, or it can lead to mutations, deletions and amplifications that will ultimately cause HNSCC.
In particular, it is known that the accumulation of alterations in tumor suppressor genes such as TP53 and CDKN2A, or PI3K–AKT–mTOR and RAS–MAPK signal pathways is associated with HNSCC onset, progression and poor prognosis.
Epigenetic also plays a role in HNSCC development, in fact this type of cancer is generally characterized by hypermethylation and thus down-regulation of important tumor suppressor genes ( CDKN2A, RARB, DCC and MGMT).
It has also been shown that the altered expression of some signaling proteins plays a role in HNSCC. For example, EGFR results over-expressed in 80–90% of HNSCCs and is associated with poor survival. It also appears that the over-expression of IL-6 and its receptor is associated with HNSCC patients’ poor prognosis. At the same time, the amplification of CCND1 and the resulting over-expression of cyclin D1, is implicated in the progression from dysplasia to carcinoma and with poor prognosis.
The clinical aspect of the choice of treatment often depends on the location and stage of the tumor, as well as the patient’s age and health condition. However, HNSCC is usually treated with surgery, radio-, chemo-, targeted- and immune- therapy, but results are often inferior to expectations.
The first-line treatments for this type of cancer are usually surgery, radio- and chemo- therapy.
However, surgery can affect the patient’s appearance, as well as their ability to chew, swallow, or talk. In the case of HNSCC located in the larynx, after surgery the neck and throat can feel numb. Those patients who undergo radiotherapy can display head and neck irritation, dry and sore mouth, difficulties in swallowing, changes in taste, nausea and inability to fully open their mouth. Radiations can also cause face swelling and chin drooping.
Some of these side effects can improve over time, but in many patients they become long-term side effects associated with their survival. In fact, around 68% of survivors report voice problems even after 10 years from radiotherapy, while around 50% of patients who underwent radiotherapy display permanent swallowing impairment.
Patients who have been treated for head and neck cancers, have an increased probability to develop a second primary cancer in the lungs, esophagus or once more in the head and neck. For these people the decision about the best treatment depends on the patient’s prior treatment history and its results, comorbidities, symptoms, and goals for treatment. It must also take into account Programmed Death Ligand 1(PD-L1) expression on tumor and immune cells.
The most popular strategy for metastatic HNSCC is immunetherapy with the immune checkpoint inhibitor Pembrolizumab, an IgG4 humanized antibody for Programmed cell Death protein 1 (PD-1), administered alone or with chemotherapy. However, some patients might not be eligible for first-line Pembrolizumab therapy, because they don't express PD-L1 or because they are at high risk for autoimmune complications. For these patients, the alternative therapy is the combined administration of Cisplatin or Carboplatin-based chemotherapy, with Cetuximab.
Unfortunately, often immunetherapies are ineffective with a response rate of around 30%. Moreover, in EU these drugs are administered as palliative therapy, thus as a very last stand.
HNSCC tumors are often highly infiltrated by immune cells, but their microenvironment is notoriously immunesuppressive. Moreover, mechanisms such as the downregulation of apoptosis, tumor immune evasion, inability of T-cells to enter the tumor or their exhaustion/inactivation, limit the therapeutic options.
Current treatments for HNSCC display poor results showcasing a tremendous need to look for novel approaches, as well as aid clinicians in choosing the best possible therapy for each patient and more easily select candidates that could benefit from immunetherapies.
In this context, we aim to identify novel biomarkers and therapeutic targets that could be used in the future to monitor clinical trials, patient selection for immunetherapies, and the design of new immunetherapeutic drugs.
One of our lines of research focuses discovering new immune prognostic tools, in particular investigate the role of neutrophils as a prognostic factor and their role in the cancer progression.
We also aim to discover HNSCC neo-antigens that can be used as therapeutic targets, and in this context investigate whether immune checkpoint inhibitors can be an effective new therapy modality.
However, we think it’s also important to answer the many questions left open concerning current therapies’ inefficacy, and thus we also aim to identify the resistance mechanisms to immunetherapies and try to improve the patients’ response to them.