Background: Colorectal cancer (CRC) has a disproportionate impact on African Americans (AA). In CRC, AA often display more aggressive disease with poorer prognosis compared to Caucasian Americans (CA). The biological mechanisms involved in the observed racial disparities are not clear but it is strikingly evident that immune responses are critical towards the development, growth and metastasis of this tumor type. Anti-tumor immunity, characterized by anti-tumor TH1 cells and strong cytotoxic T lymphocyte (CTL) activity, has been shown quite elegantly in the literature to significantly improve disease-free survival in CA patients with CRC. Unfortunately, these studies have not included patients from various ethnic backgrounds, such as AA patients, although there is no reason at this time to believe that the role of anti-tumor immunity in protection of patients from their disease will be limited to CA patients. The proposed immune mechanism of the protection is the elimination of metastatic cells breaking away from the primary tumor, decreasing tumor recurrence. We hypothesize deficiencies in anti-tumor immunity may contribute to the racial disparity observed in CRC.
Methods: We have used immunohistochemistry (IHC) on ~250 archived CRC samples from the North Carolina Colon Cancer Study to evaluate immune cell infiltration (CD8 and CD57), CTL activity (granzyme B, (GzmB)), and IL-17 production in situ. Also, using GzmB immunostainings, we analyzed the histological location of CTL activity, whether it was intratumoral vs. at the invasive borders of the CRC patient samples. The advantage of this population-based study that covered 33 counties in North Carolina is that 45% of the participants were AA while 55% were CA (self-proclaimed). The disadvantage to this study is that no follow-up data is available. All samples were tested for MSI and no MSI tumors were included in this study.
Results: Our data reveal that the number of infiltrating CD8+ and CD57+ immune cells, as well as the number of cells making IL-17, do not vary statistically by race in these CRC samples. However, analyses of the histological location for infiltrating CTL activity revealed that the frequency of CA patients that are “high GzmB” responders (in the upper 50%) is significantly higher than AA in both the intratumoral regions (p=0.01) and the invasive borders (p=0.0003). In addition, we have seen that race may modulate the effect of IL-17 on anti-tumor immunity. When IL-17 is high, both races show a good correlation between GzmB expression and the presence of intraepithelial CD8+ immune cells (0.80 and 0.82 for AA and CA, respectively). When IL-17 is low, however, this association seems to break down in AA but not in CA patients (0.53 vs. 0.88, respectively; the results reach marginal statistical significance at p=0.077). The data suggest that when IL-17 levels are low, AA patients do not have as much GzmB expression in their infiltrating immune cells as CA patients. Further studies to investigate the role of IL-17 and how it might influence anti-tumor immunity by race are definitely warranted.
Conclusion: Our data to date indicate that the number of AA patients with high numbers of GzmB expressing cells infiltrating their tumors in intratumoral as well as invasive border regions is significantly lower than what is observed in CA patients. In addition, IL-17 may have a modulatory effect on anti-tumor cytotoxicity by race. These observations support our hypothesis that immune processes may contribute to the racial disparities observed in colorectal cancer.
Acknowledgements: The authors acknowledge the contributions of R Basa, V Davies, X Li, B Murali, J Shah, B Yang and M Kinseth to these studies. This study was funded by the NCI Comprehensive Partnerships to Reduce Cancer Health Disparities (CPRCHD) grants (U54CA132384 and U54CA132379) and by 1U01CA162147 (to KLM and JMC).
Citation Format: Mohammad W. Khan, Mengxi Tian, John M. Carethers, Kathleen L. McGuire. Immune mechanisms and racial disparities in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A76.
- ©2015 American Association for Cancer Research.