Abstract IA09: IL-17 and GMCSF may be novel markers for detection of ICC
Authors: Hoyo Cathrine , Vidal Adriana , Bartlett John , Oneko Olala , Musselwhite Laura , Maguire Rachel , Obure Joseph , Mlay Pendo , Murphy Susan 
Published: October 2015

Abstract
Ethnic/Racial differences in invasive cervical cancer incidence and mortality
Despite major reductions in incidence and mortality over the last decade, an estimated half million cases of invasive cancers of the uterine cervix (ICC) continue to be diagnosed annually worldwide with 12,340 of these cases occurring in the United States. The highest incidence is in Hispanic and African American and lowest in European American women 1,2. Liquid-based cytology screening rates, whether self-reported or estimated from insurance claims data, accounted for most of the overall decline in incidence and mortality, but are comparable among African Americans, Hispanics and European Americans and thus fail to explain the racial/ethnic disparity in ICC incidence and mortality 3-5.
Ethnic/race differences in HPV distribution in Africa and the US
Reasons for continued racial/ethnic disparities in ICC incidence and mortality are still unclear, although published data in the last few years suggest that among women with cancerous lesions, women of African descent may harbor human papillomavirus (HPV) genotypes distinct from those found in women of European descent 6-8 and may be more likely to be infected with genotypes not covered by the vaccine. Among Tanzanian women, we previously found that HPV 35, 45, and 31, in addition to HPV 16 and 18, were the genotypes more frequently found in ICC cases 9. Among African Americans with CIN in North Carolina, we also found that HPV 35, 45, and 31, in addition to HPV 16 and 18 were the most common genotypes. Data suggesting that HPV 35, 45, and 31 were common genotypes in women of African descent were recently confirmed using cervical scrapes obtained from Haiti and oral lavage in the US. While HPV genotypes 45, 58 and 68 are part of the nonavalent vaccine currently in Phase III clinical trials, HPV35 is not. The singular importance of high-risk HPV 68, 35 and 58, as well as co-infections with multiple HPV types remains unclear, these findings support that some of the racial differences seen in high-grade CIN, and perhaps ICC, may be due to the different genotypes inherent to different ethnic groups. Together, these intriguing findings raise the question of what the population attributable risk of HPV 35 is, and whether it ultimately is worth adding HPV 35 to the vaccine to reduce disparities in cervical cancer incidence and mortality.
Differences in immune response to HPV genotypes may explain race/ethnic differences
A key question is whether race/ethnic differences observed are the consequence of a higher propensity for infection with specific HPV type variants in different race/ethnic groups. If so, this may suggest differences in immunological response to HPV or co-infections. It is known that infection with high risk HPV genotypes initiate a local Th2 inflammatory response at an early stage, which fosters an immunosuppressive microenvironment that contributes to tumor progression 10. Paradkar et al. 11, summarized recent data on cytokine dysregulation in cervical cancer, raising the possibility of using distinct inflammatory cytokines as biomarkers to assist in the early diagnosis of HPV-infected women at high risk of developing cancer. The goal of the present analysis is to determine if cytokines/chemokine expression differs in HPV-infected women with high risk HPV16 and/or 18 genotypes compared to women with other genotypes.
Methods
The MilliPLex MAP Human Cytokine/Chemokine immune assay kit (Millipore Corporation, Billerica, MA) was used to measure 30 chemokines and cytokines in flash-frozen ICC tissue specimens obtained from 40 women recruited from Kilimanjaro Christian Medical Center, Tanzania.
Results
In these African women, 65% (95% confidence limits, 55%-87%) of ICC tissue samples harbored HPV16 and 18. Among the 30 cytokines and chemokines measured in homogenized cervical cancer tissues, pro-inflammatory cytokine/chemokine levels differed by HPV16/18 status. In general, pro-inflammatory cytokines/chemokine levels were higher in women infected with HPV 16/18 compared to those infected with other HPV genotypes. After adjusting for age, parity and cigarette smoking, 4 cytokines remained significantly differentially expressed in ICC harboring HPV 16/18 vs. ICC without HPV16/18: IL-10 (p=0.037), IL-15 (p=0.041), IL-17 (p=0.0006), and GMCSF (p=0.0036),. To adjust for multiple comparisons, a bonferroni correction was applied and IL-17 remained significant (p=0.05).
Conclusion
These findings are consistent with IL-17 increased expression being associated with cervical cancer cell growth in tissue 11. Increased levels of IL-10, one of the best-studied Th2 type cytokines which has a general immunosuppressive function 12, have been associated with high-grade cervical lesions 13-15. Furthermore, Scott et. al., [9], reported that significantly increased levels of MIP-1a, TNF, IL-12 and IL-10 cytokines were associated with a reduced likelihood of HPV clearance among women with incident HPV infections, but without cervical intraepithelial neoplasia (CIN). While the small sample size limits inference, our data support further evaluation of, IL-17 and perhaps GMCSF as novel biomarkers of HPV16/18 related ICC.
Citation Format: Cathrine Hoyo, Adriana Vidal, John Bartlett, Olala Oneko, Laura Musselwhite, Rachel Maguire, Joseph Obure, Pendo Mlay, Susan Murphy. IL-17 and GMCSF may be novel markers for detection of ICC. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA09.