Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour–node–metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies. Head and neck squamous cell carcinomas (HNSCCs) originate from the mucosal epithelium in the oral cavity, pharynx and larynx and are commonly associated with viral infection and tobacco use. This Primer provides an overview of the epidemiology, pathogenesis and treatment of HNSCCs of different aetiologies and the effects of the cancer and its treatment on patient quality of life.

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Head and neck squamous cell carcinoma

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.

Expression of tumour-specific antigens underlies cancer immunoediting

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Cancer immunotherapy based on immune-checkpoint inhibition or adoptive cell therapy has revolutionized cancer care. Nevertheless, a large proportion of patients do not benefit from such treatments. Over the past decade, remarkable progress has been made in the development of 'next-generation' therapeutics in immuno-oncology, with inhibitors of extracellular adenosine (eADO) signalling constituting an expanding class of agents. Induced by tissue hypoxia, inflammation, tissue repair and specific oncogenic pathways, the adenosinergic axis is a broadly immunosuppressive pathway that regulates both innate and adaptive immune responses. Inhibition of eADO-generating enzymes and/or eADO receptors can promote antitumour immunity through multiple mechanisms, including enhancement of T cell and natural killer cell function, suppression of the pro-tumourigenic effects of myeloid cells and other immunoregulatory cells, and promotion of antigen presentation. With several clinical trials currently evaluating inhibitors of the eADO pathway in patients with cancer, we herein review the pathophysiological function of eADO with a focus on effects on antitumour immunity. We also discuss the treatment opportunities, potential limitations and biomarker-based strategies related to adenosine-targeted therapy in oncology.

The adenosine pathway in immuno-oncology

Fibroblasts play an essential role in organogenesis and the integrity of tissue architecture and function. Growth in most solid tumors is dependent upon remodeling 'stroma', composed of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), which plays a critical role in tumor initiation, progression, metastasis, and therapeutic resistance. Recent studies have clearly established that the potent immunosuppressive activity of stroma is a major mechanism by which stroma can promote tumor progression and confer resistance to immune-based therapies. Herein, we review recent advances in identifying the stroma-dependent mechanisms that regulate cancer-associated inflammation and antitumor immunity, in particular, the interactions between fibroblasts and immune cells. We also review the potential mechanisms by which stroma can confer resistance to immune-based therapies for solid tumors and current advancements in stroma-targeted therapies.

Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive, multi-factorial tumors in the upper aerodigestive tract affecting more than half a million patients worldwide each year. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCCs. Current treatment options for HNSCCs are surgery, radiotherapy, chemotherapy, or combinatorial remedies. Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of HNSCCs remained ∼40-50% largely due to poor availability of effective therapeutic options for HNSCC patients with recurrent disease. Therefore, there is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets. With recent technological advances in genomic and epigenetic analyses, our knowledge of HNSCC molecular characteristics and classification has been greatly enriched. Clinical and genomic meta-analysis of multicohort HNSCC gene expression profile has clearly demonstrated that HPV+ and HPV- HNSCCs are not only derived from tissues of different anatomical regions, but also present with different mutation profiles, molecular characteristics, immune landscapes, and clinical prognosis. Here, we briefly review our current understanding of the biology, molecular profile, and immunological landscape of the HPV+ and HPV- HNSCCs with an emphasis on the diversity and heterogeneity of HNSCC clinicopathology and therapeutic responses. After a review of recent advances and specific challenges for effective immunotherapy of HNSCCs, we then conclude with a discussion on the need to further enhance our understanding of the unique characteristics of HNSCC heterogeneity and the plasticity of immune landscape. Increased knowledge regarding the immunological characteristics of HPV+ and HPV- HNSCCs would improve therapeutic targeting and immunotherapy strategies for different subtypes of HNSCCs.

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Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy.

CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73hi population in human colorectal cancers (CRCs) and two CD73- murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A2A and A2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A2B-mediated ADO-CAF-CD73 feedforward circuit and A2A-mediated immune suppression is crucial for improving therapeutic outcomes.

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CD73 on cancer-associated fibroblasts enhanced by the A 2B -mediated feedforward circuit enforces an immune checkpoint

e17549 Background: Ovarian cancer is the most lethal gynecologic cancer with roughly 20% of cases attributable to mutations in BRCA 1 or BRCA 2. In 2018, the SOLO-1 study, comparing PARPi to placebo in BRCA 1/2 mutated ovarian cancers following first-line chemotherapy showed an unprecedented 70% reduction in the hazard to progression or death. Consequently, in 2020, ASCO published a consensus statement recommending germline testing for all women with epithelial ovarian cancer. Currently, our understanding of the improvement, or lack thereof, in germline testing for ovarian cancers following these changes are not well described, and research is needed to determine the real-world frequency of and barriers to genetic testing. Methods: We retrospectively reviewed 115 patients’ charts with newly diagnosed ovarian cancer from 2012-2022 at Grady Memorial Hospital. An assessment of genetic testing was acquired, including genetic counseling referral frequency, attrition, somatic tumor testing, and mutated genes identified. Additional characteristics including age, race, histology, grade, and stage were obtained. Univariate association (Chi-square or Fisher’s exact test) was performed to correlate the above variables with germline testing. Results: Of 115 patients diagnosed with ovarian cancer from 2012–2022, 33% received a genetic counseling referral and 16.5% received an evaluation. Germline testing, in lieu of referral, was ordered by the physician in 20% of cases. Among patients who completed germline testing, a pathogenic mutation was found in 9.8% of patients. Patients who were ≤ 48 years old were more likely to be referred for genetic counseling (50% vs. 26.5%, p = 0.016), and those with earlier stage disease (stage 1 or 2 versus stage 3 or 4) were more likely to be referred for genetic counseling (46.5% vs. 25%, p = 0.018). There was a significant difference in those receiving genetic counseling referral pre and post October 2018 (when SOLO-1 was published) with 50% of patients being referred after October 2018 versus 18% of patient before referred prior (p = 0.005), and in 2021 (following the ASCO consensus statement), an impressive 63.6% of patients were referred with attrition rate of 54.5%. Conclusions: Our real-world data demonstrates improvement in germline testing for newly diagnosed ovarian cancers at our institution over the past decade, with significant increases in both genetic counseling referral and attrition since 2018. Despite these improvements, we continue to be deficient in testing patients who are older and with more advanced-stage disease, which may be due to the gravity of their presentation and prioritized focus of treatment initiation. System-wide changes, including the option of having genetic testing ordered by the oncologist in the clinic with genetic counseling performed after results are available, are being explored.

Genetic counseling referral frequency and attrition for newly diagnosed epithelial ovarian cancer at Grady Memorial Hospital from 2012-2022.

e24046 Background: Immunotherapy (IO) is now an integral part of treatment for most patients with triple negative breast cancer (TNBC). The mechanism of action and associated side effects of IO differ significantly from conventional chemotherapy and patient comprehension of these novel treatments can be difficult to assess. Previous research has demonstrated that patient understanding of anti-cancer treatments is hindered by multiple barriers including education level and healthcare literacy. Standardized educational tools to improve patient comprehension of immunotherapy are integral to improving patient engagement with their treatment plan and providing informed consent. Methods: This is a prospective pilot study investigating the efficacy of standardized educational materials (2 animated videos and 1 pamphlet) to improve patient comprehension of IO. Patients with TNBC were recruited from Emory University between 2021-2022 and were asked three questions related to their understanding of the immune system, immunotherapy, and IO-related side effects before and after viewing the educational tools. Audio-recordings of the patients’ answers were coded as correct or incorrect by two independent reviewers using the video’s definitions as the standard. Clopper-Pearson method and exact McNemar’s test were used to calculate pre- and post-education correct definition rates and paired rates, respectively. Multivariate analyses were conducted investigating the impact of age, highest level of education, and race on patient comprehension. Results: 46 patients with TNBC were enrolled with mean age of 57 years (range 27-84 years). The majority of patients were Black (65%), while the remaining patients were Non-Hispanic White (30%) or unknown (5%). Highest level of education was reported as high school (13%), undergraduate (61%), and graduate school (26%). Comprehension of the terms "immune system" and "immunotherapy" significantly improved after viewing the patient educational material with an increase in correctly defining these terms from 50% to 89.1% (p-value < 0.01) and 41.3% to 82.6% (p-value < 0.01), respectively. Patients' ability to describe two or more side effects of IO also increased from 11% to 87% post-education (p-value < 0.01). Patients with graduate degrees had a 4.24 times greater odds of correctly answering the questions compared to those with undergraduate or high school degrees (p-value 0.057). There were no differences in patient comprehension by race or age. Conclusions: Patient education on novel therapeutics in cancer care including immunotherapy presents a challenge to providers given time constraints in clinic and lack of standardized educational resources. Through easily implemented patient education, we were able to significantly improve patient comprehension of immunotherapy and IO-related side effects in a diverse population of patients with TNBC.

Madison Canning

Papers

Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy.

CD73 on cancer-associated fibroblasts enhanced by the A 2B -mediated feedforward circuit enforces an immune checkpoint

Genetic counseling referral frequency and attrition for newly diagnosed epithelial ovarian cancer at Grady Memorial Hospital from 2012-2022.

Patient understanding of immunotherapy and its side effects for women with triple negative breast cancer.

CDK4/6 Inhibition in the Metastatic Setting: Where Are We Headed?