Role of PD-1/PD-L1 pathway in the development of Head and neck squamous cell carcinoma (HNSCC)

The human immune system has the innate capability to recognize and eliminate cancer cells. However, cancers can grow progressively by evading recognition by the immune system or by suppressing its cytolytic activity. Cancer cells employ both mechanisms through various ways during the escape phase of immunoediting.1 Cancers can:

• minimize recognition through reduced antigen presentation
• develop resistant variants under selective pressure
• express proteins to boost resistance
• produce cytokines that suppress the immune system
• enhance angiogenesis
• suppress the immune system by expressing complementary ligands to immune checkpoints

Restoring the anti-tumor immune response is an important cancer treatment strategy. One of the most effective means to accomplish this has been to reverse immune tolerance by blocking the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Hence, the development of immune checkpoint inhibitors (ICIs) is considered a revolutionary milestone in the field of immuno-oncology.2

Various mechanisms of immune evasion, including the PD-1/PD-L1 pathway, play a key role in the development and progression of HPV-positive HNSCC.3 In fact, the formation of HPV+ HNSCC is mainly due to PD-1/PD-L1 activation.3

PD-1 and PD-L1 roles

PD-1 is a regulatory molecule expressed by activated T-cells. The binding of PD-1 to its complementary ligand, PD-L1, activates the signaling of PD-1 receptors which inhibits T-cell proliferation, cytokine generation and release, and antitumor activity.4 PD-1 expression is induced in many cell types in response to inflammation, caused by bacterial or viral infections, which leads to an increased expression of CD8+ T cells and CD4+ helper T cells to fight pathogens.5

PD-L1 is a transmembrane protein expressed in normal tissues to inhibit the activity of T-cells.6 The main role of the PD-1/PD-L1 pathway is to serve as “immune checkpoints” and prevent autoimmunity and excessive tissue destruction.4 While Interferon-gamma (IFN-γ) is considered the primary cytokine that triggers PD-L1 expression, several additional cytokines in the tumor microenvironment (TME), e.g., Interleukin-1⍺ (IL-1⍺), IL-10, IL-27 and IL-32 can upregulate PD-L1 expression.7

PD-1/PD-L1 binding regulates both the initiation and maintenance of T-cell tolerance and persistent antigen expression.8 It is responsible for a wide range of immune responses directed against tumors, pathogens, and self-antigens. Upregulation of PD-L1 interferes with proliferation of tumor-specific cytotoxic T cells and induces T cell exhaustion and apoptosis. PD-L1 limits the expansion of CD8+ T cells but does not affect their cytolytic activity.9

Conditions conducive to growth of pathogens causing HNSCC

Microorganisms need suitable conditions to grow and thrive. Tonsils are gland-like structures in the back of the throat that help trap bacteria and viruses. They contain lymphocytes to protect the body from infections. Since they frequently harbor foreign debris and bacteria, their single-layered epithelium can easily uptake and incorporate exogenous material and alter the cells.10 These transformed cells can promote expression of PD-L1 which binds to PD-1 receptors inhibiting T cell activation and proliferation and allows cancer cells to evade immune checkpoints. This leads to persistent HPV infection and tumorigenesis. Furthermore, in tonsillar crypts, an enclosed biofilm of bacteria can form inside a matrix to protect HPV from the immune system.11 Conversely, the stratified epithelium of the oral cavity, which is also easily infected with HPV, is less susceptible to transformation and onset of carcinogenesis.10

Checkpoint molecules and cancer immunotherapy

PD-1 and Cytotoxic T-lymphocyte antigen 4 (CTLA-4) are two checkpoint molecules that suppress T-cell-mediated immune responses, leading to the development of tumors.12 PD-L1 is expressed on the surface of tumor cells and antigen-presenting cells in various solid tumors, including head and neck cancer.13 PD-1 is expressed on the surface of immune-related lymphocytes, such as T-cells, B-cells, and myeloid cells.14

Cancer immunotherapy is a specific method to eliminate cancer cells by enhancing the host immune system. Since PD-1/PD-L1 pathway is known to downregulate T-cell antitumor activity, monoclonal antibodies that inhibit either PD-1 or PD-L1 will reverse this immune suppression.15 This emerging paradigm in antitumor immunotherapy involves rejuvenating immunity by inhibiting the inhibitors that are responsible for silencing T-cells. It is believed that therapeutic interventions that overcome immune suppression may be more efficacious long-term than utilizing approaches that boost immunity, which are generally short-lived.9

References

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Key differences between HPV-positive and HPV-negative head and neck squamous cell carcinomas (HNSCC)

Head and neck squamous cell carcinomas (HNSCC) develop from the mucosal epithelium in the oral cavity, pharynx, and larynx and are the most common malignancies that arise in the head and neck.1 Increasingly, tumors in the oropharynx are linked to prior infection with oncogenic strains of human papillomavirus (HPV), primarily HPV-16 and, to a lesser extent HPV-18 and others.2,3 HNSCCs of the oral cavity and larynx are primarily associated with tobacco-derived carcinogens, excessive alcohol consumption, or both, and are collectively referred to as HPV-negative HNSCC.4 The median age of diagnosis for non-virally associated HNSCC is 66 years, whereas the median age of diagnosis for HPV-associated oropharyngeal cancer is about 53 years.5

HPV-positive and HPV-negative HNSCC are two distinct diseases with different sites of origin, etiological agents, risk factors, and contributions to the development of oropharyngeal squamous cell carcinoma (OPSCC). The demographics, cause, and prevalence of HPV-positive and NPV-negative cancers are summarized in Table 1.

Table 1: Demographics, Cause, and Prevalence of HNSCC.

Whereas the incidence of smoking-related HNSCC continues to decline worldwide, that of HPV-positive HNSCC is on the rise.6 During 2007-2016, HPV-associated cancers increased by 2.1% per year on average, whereas cancers not associated with HPV decreased by 0.4% per year on average.6

HPV-positive and HPV-negative HNSCCs present with different molecular characteristics, immune landscapes, and clinical prognosis (Table 2) and lead to two fundamentally different diseases with distinct pathogenesis in terms of gene expression, tumor microenvironment (TME), and mutational burden.

Table 2. Pathology and Disease Signature in HNSCC.

Genomic and epigenetic analyses reveal extremely high heterogeneity in HNSCC in terms of characteristic mutations, molecular signature, cellular phenotype, composition of TME, and immune landscape (Table 3).

Table 3. Characteristic mutations in HPV-positive and HPV-negative HNSCC.

Various promising vaccine targets have been identified and treatment options employed for the treatment of HPV-positive and HPV-negative cancers with varying degrees of success (Table 4).

Table 4. Treatment options and targets.
Treatment personalization and de-escalation

According to Dr. Nishant Agrawal, Chief of Otolaryngology-Head & Neck Surgery UChicago Medicine, “We have seen a significant increase in the incidence of HPV-associated oropharyngeal cancer in relatively younger patients, with the median age of diagnosis in the 50s, even patients in their 30s.”32 He added that “Even at 2 years after radiation therapy, 15% of patients had grade 2 swallowing dysfunction and 8% had progressive dysphagia, so their swallowing is going to continue to get worse. Patients may also have chronic xerostomia. The dry mouth improves but it never gets back to 100%.”33 In contrast to patients with HPV-negative HNSCC, who have a five-year survival rate of about 25%-40%, patients with HPV-positive HNSCC fare much better with a disease-free survival rate of 85%-90% over five years. According to Dr. Agrawal, the better prognosis for HPV-positive patients suggests a need to de-escalate treatment while preserving survival.

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  33. https:\\ascopost.com\\issues\\april-25-2017\\deintensifiying-treatment-of-hpv-positive-oropharyngeal-cancer-could-reduce-toxicity-while-maintaining-function-and-survival