Tumor Immunology: Genetics, Immune Responses and Racial Disparities in Cancer
Colorectal cancer: the role
of immune responses in tumor aggressiveness, metastasis, and racial
disparities. Colorectal cancer (CRC) is the third leading cause of cancer-associated deaths in developed countries. Multiple different forms of genomic instability are associated with CRC. Chromosomal instability is a common form, found in about 80-85% of spontaneous tumors. Microsatellite instability (MSI), caused by defects in DNA mismatch repair, is found in ~15-20% of colorectal cancers. MSI tumors are associated with greater survival in patients because the tumors are less aggressive and metastasize less frequently. Elevated microsatellite instability associated with select tetranucleotide repeats (EMAST) is due to defects in the activity of the msh3 mismatch repair protein and appears to be found in more aggressive tumors. Recent studies have demonstrated that anti-tumor immune responses characterized by tumor-specific cytotoxic cells improve patient prognosis in CRC no matter what type of genomic instability is observed. Interestingly, a race disparity is also observed in CRC with a higher incidence occurring in African Americans (AA). AA patients tend to have more aggressive disease with a worse prognosis than Caucasians (CA) as well. While diet, socioeconomic status, and access to healthcare contribute to racial disparities, we are showing that biological factors, such as immune responses and genetics, also play a role. Our collaborator, John Carethers, and his colleagues have demonstrated that AA patients with CRC exhibit 50% less MSI than CA. In addition, we have shown that EMAST is more frequent in AA than CA in rectal cancer. These observations are significant because MSI tumors are less aggressive, while tumors with EMAST are more aggressive. Interestingly, both of these genetic abnormalities are associated with heavy immune cell infiltration into the tumors, so some immune responses make the tumors more aggressive while others render them less so. We have now shown that even with equal presence of CD8+ and CD57+ immune cells in their tumors, AA had a lower cytotoxic response against the tumor as compared to CA. Our future studies include looking at different pathways that may be responsible for the observed lower cytotoxicity in AA using various techniques, including an analysis of inflammatory responses in the tumor. Studying genomic instabilities and their corresponding immune responses will lead to a better understanding not only of racial disparities but also aggressive CRC in general, thus leading to more effective CRC therapeutics in the future.
Prostate cancer: the role of cytoskeletal remodeling, extracellular matrix, and cell adhesion in prostate cancer development and racial disparities. Prostate cancer (PC) is the second leading cause of cancer associated deaths among men. Race is second only to age as the highest risk factor with the incidence and mortality rates greater in AA than CA. In collaboration with Dan Mercola and his colleagues, we have re-analyzed gene chip microarray data generated by the NCI SPECS and EDRN Consortium at UCI using race as a factor to identify differential gene expression. In these studies, our results have implicated the stroma tissue of PC as the main site of altered gene expression between AA and CA. Within the stroma, genes linked to cytoskeletal remodeling (CDH5, COL4A.1, and NID1) and immune response (HLA-DMB and HLA-DPA1) are some of the most differentially expressed. Our current work on this project has two specific aims, the first being to validate these microarray analyses at the RNA level by performing qRT-PCR, and at the protein level by immunohistochemistry (IHC). For each assay, we will be using independent cohort of PC from AA and CA. The second aim of our ongoing studies is to identify and understand the biological factors, including immune/inflammatory responses, located in the stroma that affected the aggressiveness of this disease and contribute to racial disparities. Our research will lead not only to a better understanding of the causes underlying the racial disparities in PC but also will help identify clinically relevant factors that can be evaluated for future therapies.
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Lee, S.-Y., K. Miyai, H. S. Han, D.-Y. Hwang, M. K. Seong, H. Chung, B. H. Jung, B. Devaraj, K. L. McGuire, J. M. Carethers. 2012. Microsatellite instability, EMAST, and morphology associations with T cell infiltration in colorectal neoplasia. Dig Dis Sci. 57:72-78.
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