Abstract
Oropharyngeal squamous cell carcinoma (OPSCC) incidence is increasing at a nearly epidemic rate, largely driven by the human papillomavirus (HPV). Despite the generally favorable clinical outcomes of patients with HPV driven (HPV+) OPSCC, a significant subset of HPV tumors associated with tobacco exposure have diminished treatment response and worse survival. The tumor immune microenvironment (TIME) has been shown to be a critical driver of treatment response and oncologic outcomes in OPSCC generally and HPV+ OPSCC more specifically. However, the impact of tobacco exposure on the TIME in OPSCC patients remains unclear. We analyzed the relationship between TIME, tobacco exposure and clinical outcomes in OPSCC patients (n = 143) with extensive tobacco exposure (median pack-years = 40). P16 overexpression, a surrogate marker of HPV association, was a strong predictor of relapse-free (RFS) and overall survival (OS) (p < 0.001, p < 0.001 respectively) regardless of tobacco exposure and associated strongly with differential infiltration of the tumor by both CD3 and CD8 lymphocytes measured via immunohistochemistry (p < 001, p < 0.001 respectively). CD3 and CD8 infiltration was a strong predictor of RFS and OS and associated strongly with disease stage (AJCC 8th Edition Staging Manual). Tobacco exposure correlated significantly (p < 0.001) with decreased CD8 infiltration in p16+ OPSCC tumors. Our findings demonstrate that the HPV+ OPSCC clinical outcomes are strongly correlated with the TIME, which is potentially modulated by tobacco exposure. Immunomodulatory strategies targeting this disease in smokers must take into consideration the potential modifying effects of tobacco exposure on treatment effectiveness and clinical outcomes.
Highlights
Tumor immunity has been shown to be a critical driver of tumorigenesis, treatment response and clinical outcomes in multiple solid tumor types including head and neck squamous cell carcinoma (HNSCC)
In the current study we evaluated the relationship between aspects of the tumor immune microenvironment (TIME) (CD3 and CD8 lymphocytes) and clinical outcomes in intermediate risk Oropharyngeal squamous cell carcinoma (OPSCC) patients (HPV+ smokers)
Veteran’s Administration (MEDVAMC) Institutional Review Boards, we reviewed the records of Veterans with previous untreated oropharyngeal squamous cell carcinoma (SCC) between January 1, 2000 and January 1, 2012
Summary
Tumor immunity has been shown to be a critical driver of tumorigenesis, treatment response and clinical outcomes in multiple solid tumor types including head and neck squamous cell carcinoma (HNSCC). Among HNSCC sites, SCC of the oropharynx, associated with the human papillomavirus (HPV+ OPSCC) is increasing at a nearly epidemic rate across the United States[1,2,3,4,5,6] Mediated malignancies such as HPV+ OPSCC demonstrate increased tumor immunity, which is thought to contribute to differential treatment response[7,8,9,10]. A majority of new OPSCC diagnoses are thought to be driven by HPV, a significant number of patients demonstrate a history of significant tobacco exposure, a known carcinogenic risk factor for OPSCC and a critical modulator of overall patient health[1,2,3,4,5,6] In these patients, clinical outcomes are worse compared to those of non-smoking OPSCC patients[1,5,6,11,12]. In the current study we evaluated the relationship between aspects of the TIME (CD3 and CD8 lymphocytes) and clinical outcomes in intermediate risk OPSCC patients (HPV+ smokers)
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