Immunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity

JNCI: Journal of the National Cancer Institute, Mar 2019

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with high morbidity and mortality. Racial disparity in HNSCC is observed between African Americans (AAs) and whites, effecting both overall and 5-year survival, with worse prognosis for AAs. In addition to socio-economic status and demographic factors, many epidemiological studies have also identified factors including coexisting human papillomavirus (HPV) infection, primary tumor location, and a variety of somatic mutations that contribute to the prognostic incongruities in HNSCC patients among AAs and whites. Recent research also suggests HPV-induced dysregulation of tumor metabolism and immune microenvironment as the major regulators of HNSCC patient prognosis. Outcomes of several preclinical and clinical studies on targeted therapeutics warrant the need to elucidate the inherent mechanistic and population-based disparities underlying patient responses. This review systematically reports the underlying reasons for inconsistency in disease prognosis and therapy responses among HNSCC patients from different racial populations. The focus of this review is twofold: aside from discussing the causes of racial disparity, we also seek to identify the consequences of such disparity in terms of HPV infection and its associated mutational, metabolic, and immune landscapes. Considering the clinical impact of differential patient outcomes among AA and white populations, understanding the underlying cause of this disparity may pave the way for novel precision therapy for HNSCC.

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Immunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with high morbidity and mortality. Racial disparity in HNSCC is observed between African Americans (AAs) and whites, effecting both overall and 5-year survival, with worse prognosis for AAs. In addition to socio-economic status and demographic factors, many epidemiological studies have also identified factors including coexisting human papillomavirus (HPV) infection, primary tumor location, and a variety of somatic mutations that contribute to the prognostic incongruities in HNSCC patients among AAs and whites. Recent research also suggests HPV-induced dysregulation of tumor metabolism and immune microenvironment as the major regulators of HNSCC patient prognosis. Outcomes of several preclinical and clinical studies on targeted therapeutics warrant the need to elucidate the inherent mechanistic and population-based disparities underlying patient responses. This review systematically reports the underlying reasons for inconsistency in disease prognosis and therapy responses among HNSCC patients from different racial populations. The focus of this review is twofold: aside from discussing the causes of racial disparity, we also seek to identify the consequences of such disparity in terms of HPV infection and its associated mutational, metabolic, and immune landscapes. Considering the clinical impact of differential patient outcomes among AA and white populations, understanding the underlying cause of this disparity may pave the way for novel precision therapy for HNSCC. Head and neck cancer squamous cell carcinoma (HNSCC) is the sixth-most common cancer worldwide, estimated to comprise approximately 3% of all cancers in the United States. In 2018, approximately 51 540 new cases are projected and 10 030 people are expected to die of oral cavity and pharynx cancer in the United States alone (https://seer.cancer.gov/). Despite considerable efforts, the 5-year overall survival (OS) rate of HNSCC patients has not improved substantially in several decades. The median age at diagnosis of the disease is approximately 63 years (1), although initial disease presentation at younger age is on the rise (2). Generally, HNSCC develops in the upper aero-digestive tract of the head and neck, which includes the oral cavity, nasal cavity, larynx, pharynx, and salivary glands. The traditional etiology of HNSCC generally involves tobacco use (either chewing or smoking) and alcohol consumption. Recent epidemiological and laboratory results, however, have implicated human papillomavirus (HPV) as a causative agent for some HNSCC types. HPV generally infects the tonsillar tissue of Waldeyer’s ring. This includes the subsites of the base of the tongue and palatine tonsillar region, both components of the oropharynx. Approximately 70% of oropharyngeal cancers (OPC) in the United States are caused by HPV infection, which generally depicts the younger population as having a very distinct prognosis compared with tobacco-and alcohol-induced OPC (3). HNSCC is endemic in Southeast Asian countries, where tobacco and beetle quid chewing is a cultural norm. In the United States, tobacco remains a main risk factor in cancers of the oral cavity, larynx, and hypopharynx, but a steady downward trend has been noted in tobacco-related HNSCC as a result of proper public health management (4). Although the incidence of tobacco-related HNSCC has been reduced, HPV-induced HNSCC cases have increased considerably in recent years. Currently, about 25% of HNSCCs identified in the United States are thought to arise independent of tobacco use (5). The presence of HPV is thus an independent risk factor for OPC, and, importantly, provides an improved therapeutic response relative to HPV-negative HNSCC (6–9). Similar to other malignancies, including lung, colon, prostate, and breast, the incidence and mortality of HNSCC varies among different racial and ethnic groups (https://www.cdc.gov/cancer/dcpc/data/race.htm) (10–12). Successful detection and understanding of the risk factors associated with this disparity is critical for control and management of the disease and for overall better patient outcome. The African American (AA) population with HNSCC has a poorer prognostic outcome and higher mortality rate than the whites (13,14). However, there are differences in opinion regarding the cause of differential incidence and mortality rates between the two groups. Lack of adequate health insurance coverage, socio-economic status, and HPV status are considered some of the underlying factors (15). For instance, differences in mortality in the AA and white population, particularly in OPC, may in part be due to greater overall prevalence of HPV in the white population (34%) compared with AAs (4%) (15). Although inconsistencies appear in prognosis and therapy outcomes among racial groups, it is still unclear whether the disparity is based on only genetic and demographic factor (...truncated)


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Chaudhary, Sanjib, Ganguly, Koelina, Muniyan, Sakthivel, Pothuraju, Ramesh, Sayed, Zafar, Jones, Dwight T, Batra, Surinder K, Macha, Muzafar A. Immunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity, JNCI: Journal of the National Cancer Institute, 2019, pp. 233-244, Volume 111, Issue 3, DOI: 10.1093/jnci/djy207