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.

Figure 1.

Surveillance, Epidemiology & End Results-based cancer statistics stratified by anatomic sites between African American and white head and neck squamous cell carcinoma (HNSCC) patients. A) Incidence rates per 100 000 (2010–2014) (in percentage). B) Relative 5-year survival rates (2007–2013) (in percentage) in different subsite malignancies of African American and white head and neck squamous cell carcinoma (HNSCC) patients are presented.

Figure 2.

Alterations in metabolic pathways in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma tumors. Glucose enters the tumor cells by Glucose Transporter 1 (GLUT1). Hexokinases I or II (HKI or HKII) convert glucose to glucose-6-phosphate. Pyruvate formed in the subsequent steps of glycolysis is either used for lactate generation in the cytosol or is shuttled inside the mitochondria where it is converted to acetyl-CoA by the multi-enzyme complex pyruvate dehydrogenase (PDH). Acetyl-CoA is then fed into the tricarboxylic acid (TCA) cycle in the mitochondrial matrix. Subsequent steps in the TCA cycle generate high-energy currencies nicotinamide adenine dinucleotide (NADH) and Flavin Adenine Dinucleotide (FADH₂), which are harvested in the electron transport chain (ETC) to generate adenosine triphosphate (ATP). HPV-positive tumors: HPV positive tumors are observed to express higher levels of HK I and PDH, thereby ensuring these tumor cells undergo pronounced oxidative phosphorylation (OXPHOS). Besides, higher expression of Monocarboxylate Transporter (MCT1) and Lactate Dehydrogenase B (LDHB) in these tumors helps in the sequestration of lactic acid from the tumor microenvironment and conversion of the same to pyruvate respectively. This pyruvate is utilized in the TCA cycle followed by OXPHOS, leading to higher generation of ATP molecules. HPV-negative tumors: HPV-negative tumors have higher expression of HK II and Pyruvate Dehydrogenase Kinase (PDK). PDK phosphorylates and inactivates PDH, thereby inhibiting the formation of acetyl-CoA. Pyruvate is shuttled towards lactate generation by Lactate Dehydrogenase A (LDHA). A part of the lactate is subsequently expelled to the microenvironment via MCT4. Presence of lactate in the environment results in enhanced tumor aggressiveness (details in text). Blue circles indicate molecules with higher expression and bold arrows indicate more prominent pathways in each of the tumor type.

Figure 3.

Differential immune-metabolic landscape in the human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma tumors. HPV-positive and negative tumors demonstrate varied spatial organization of the enzymes involved in aerobic glycolysis and oxidative phosphorylation (OXPHOS). The immune phenotype in these two types of tumors also vary grossly. HPV-positive tumors: HPV-positive tumors have enhanced expression of Glucose Transporter 1 (GLUT1) and Cytochrome c Oxidase subunit 5B (COX₅B) in the tumor core (red zone), resulting in enhanced mitochondrial OXPHOS in the tumor nest compared with the tumor periphery (blue zone) wherein aerobic glycolysis is more pronounced. This is speculated to propel most of the helper Cluster of Differentiation 4 (CD4)⁺ and cytotoxic CD8⁺ T cells towards the tumor interior, resulting in better anti-tumor immune infiltration. HPV-negative tumors: HPV-negative tumors demonstrate higher expression of mitochondrial respiration markers GLUT1 and COX₅B in the tumor periphery than that in the tumor core. Thus, HPV-negative tumor interiors undergo more prominent aerobic glycolysis with enhanced deposition of lactate. Higher levels of lactate are implicated in immune suppression. This may partially elucidate the rationale behind lesser anti-tumor CD4⁺ and CD8⁺ T cells but pronounced suppressive regulatory (Forkhead Box P3+ Regulatory T cells [FoxP3⁺Tregs], T-helper cell 17 [Th17]) cells in the HPV-negative tumors.