Circulating cytokines associated with survival among lung cancer patients responsive to HPV antigen stimulation
Introduction
Human papillomavirus (HPV) has been detected in lung tumors, but its role as an etiologic agent for lung cancer remains controversial. HPV infection may foster a pro-inflammatory environment that increases lung cancer risk. We sought to examine immunomodulatory effects by examining the differences in lymphocyte and cytokine profiles between lung cancer cases and HPV-vaccinated healthy controls in response to HPV antigen stimulation and their subsequent impact on survival.
Methods
Peripheral blood mononuclear cells and plasma were isolated from 54 newly diagnosed lung cancer cases and 11 healthy, HPV-vaccinated controls. Cells were exposed to cellular media and three doses of Gardasil for 20 hours as an HPV challenge. Interleukin (IL-) 4, IFN-g, and IL-17A secreting cells were then quantified using enzyme-linked immunocell spot analysis. Individuals were categorized as HPV-responsive if the HPV challenge resulted in an increase of at least two types of secreting cells, compared to media-exposed cells. Cytokine levels among HPV-responsive and HPV-non-responsive cases were compared by T-tests, and Cox proportional hazards models were used to estimate the effect of HPV response on survival.
Results
Of the 54 lung cancer patients, 20 (37.0%) were classified as HPV-responsive. Levels of IL-17A were significantly higher among HPV-responsive patients (mean=89.1 cells/106) compared to non-responsive cases (9.8 cells/106) (p=0.012). HPV-responsive patients had worse overall survival compared with non-responsive patients; however, this difference was not statistically significant (adjusted (a) HR: 2.30, 95% CI: 0.99-5.34). When stratified by smoking status, HPV-responsive smokers appeared to have a higher risk of death compared with non-responsive smokers (aHR: 1.97, 95% CI: 0.88-4.42).
Conclusion
Survival did not differ significantly between lung cancer patients who were HPV-responsive and HPV non-responsive. However, HPV-responsive patients appeared to have worse survival, which may indicate that immunoregulatory factors may be of importance in lung cancer prognosis.