Dr Sean Kimbro’s recent work explores the association between genetic variations of the innate immune system and aggressive forms of breast and prostate cancer that occur disproportionately in African Americans. These genetic variations that provided protection in an African environment unfortunately now contribute to several disease disparities, including diabetes, obesity, and breast and prostate cancer. Kimbro hopes that his findings can be applied to the development of cancer therapies that will be more effective for African Americans and other populations around the world that have been understudied and underserved.
People of African ancestry are at a higher risk of dying from certain complex diseases, including breast and prostate cancer. Complex diseases arise as a result of both biological and external/psychosocial factors, such as environment, socioeconomic status, and health behaviour. There is increasing evidence for biological differences in the progression and outcome of breast and prostate cancer. While the full extent of these biological factors is unknown, Dr Sean Kimbro has proposed that certain genetic adaptations that served to enhance the survival of those in African environments unfortunately also now contribute to complex disease disparities, including breast and prostate cancer.

Innate immunity, inflammation, and cancer

Genes related to innate immunity, which can be seen as the first line of defence, are inherited from our parents and offer immediate (rather than learned) protection from environmental stresses, such as temperature extremes, food scarcity and toxicity, and infectious agents that seek access to human hosts via a variety of routes (including skin, mouth, lungs, stomach, and gastrointestinal and urogenital tracts). Not surprisingly, a large number of innate immune genes and a large number of variations of many of those genes are necessary to counteract infectious agents (bacteria, viruses, parasites and worms), since these pathogens continue to mutate in a continuous attempt to outwit human immune defences.

“More studies are needed to test for links between complex disease disparities and specific genetic variants of the innate immune response.”

Innate immunity is a part of the inflammatory response that is a component of most complex diseases like cancer. Further, there is extensive crosstalk between inflammation and cancer, given that cancers can thrive under conditions of chronic inflammation and often subvert mechanisms of host anti-tumour immunity to support tumour progression. Based on some of his preliminary findings outlined below, Kimbro recently reviewed published evidence for relationships between innate immune gene variants (chosen for their association with disease or for their relatively high frequency among people with African ancestry) and the frequency of breast and prostate cancer risk, progression and/or mortality (Cancer Immunology Research, 2019).

Innate immunity and widespread complex disease inequality

It is important to note that cancer disparities among African Americans are not limited to breast and prostate cancer, but also include colorectal cancer in both sexes, uterine cancer in females, and stomach and lung cancer in males. Strikingly, all of these tissues are exposed to relatively high levels of infection-causing pathogens and require strong innate immune defence. Consistent with this, a large study showed that 925 sequence variants in 173 innate immune-response markers were significantly correlated with lung, ovarian, prostate, breast, and colorectal cancers.

People with African ancestry also experience higher rates of many other complex diseases, including cardiovascular disease, inflammatory and autoimmune disease, and neurological dysfunction (including diseases of the central nervous system and brain). Kimbro highlights that many more studies are needed to test for links between complex disease disparities and specific genetic variants of the innate immune response that vary in their distribution among different ethnic populations.

Inflammation and aggressive breast cancer
African American women are likely to develop more aggressive forms of breast cancer, and among the variety of breast cancer subtypes, there are several lines of evidence that aggressive forms found in African American women are linked with inflammation. First, racial inequalities in survival rates between Black, white, and Hispanic women persist only when comparing women with aggressive breast cancer, ie, breast cancer which has spread to the nearby tissue and lymph nodes or entered the bloodstream or lymphatic system. Second, small breast tumours (those of less than two centimetres) have a tendency to spread more in African American women compared to European women. Third, African Americans are more likely to develop inflammatory breast cancer resulting in a shorter lifespan when compared to European Americans. Fourth, African American women (but not Hispanic women) are linked to poor inflammatory breast cancer outcomes. Finally, a higher frequency of genetic mutations related to innate and adaptive (learned) immunity is found in breast cancer patients of African vs European descent.

African immunity and cancer disparities

Recent studies have found that people with the highest levels of African ancestry mount the strongest inflammatory response, including higher expression levels of inflammatory proteins and more effective clearance of bacteria. Many scientists have studied Toll-like receptors (TLRs) and their related proteins, and prior investigators have noted clear differences between TLR-mediated immune responses of monocytes (innate immune cells) obtained from African vs European participants.

Kimbro and his colleagues identified disease-associated gene variants of TLRs and TLR-associated proteins and explored whether any of these variants were associated with breast or prostate cancer risk in African Americans. In African American men, they found that the interaction between the rs1898830 variant of TLR2 and the rs4251545 variant of the TLR-associated kinase IRAK4 was significantly linked to prostate cancer risk. The Kimbro lab also found a link between the same rs4251545 IRAK4 variant (present in 27% of the African American population, but in only 13% of the Latino population, 11% of the Asian population, and 9% of the European population) and breast cancer risk in a small group of African American women.

“More studies are needed to test for links between complex disease disparities and specific genetic variants of the innate immune response.”

Unfortunately, the same robust immune responses used to protect against deadly pathogens, such as those found in the tropics and subtropics of Africa, Asia, and South America, may also fuel higher and more damaging levels of inflammation that exacerbate a wide range of complex diseases, including cancers, cardio-metabolic and neurological diseases. Kimbro predicts that differences in innate immunity among individuals who vary by geographic ancestry will impact susceptibility to the establishment and progression of specific types of tumours. This point of view provides a reasonable explanation for the ongoing and currently untreatable phenomenon that African Americans are more susceptible to early onset and aggressive breast and prostate cancers.

A promising path forward

As medical researchers continue to characterise the nature of ethnic differences in innate immunity and how they contribute to cancer risk and progression, treatments can be developed that more appropriately and effectively harness or modulate individual immune responses. Whereas most modern medicines in the West have been developed and optimised for people of European descent, increasing research on the role of innate immune mechanisms in disease among non-European peoples offers a promising approach which will benefit those who have been underrepresented and underserved, and yet represent the world’s majority.

References

• Hooker, S, Woods-Burnham, L, Bathina, M, et al, (2019) Genetic ancestry analysis reveals misclassification of commonly used cancer cell lines. Cancer Epidemiology, Biomarkers & Prevention, 28(6), 1003–9. doi.org/10.1158/1055-9965.EPI-18-1132
• Yeyeodu, S, Kimbro, S, LaCreis, R, et al, (2019) Protective innate immune variants in racial/ethnic disparities of breast and prostate cancer. Cancer Immunology Research, 7(9), 1384–9. doi.org/10.1158/2326-6066.CIR-18-0564
• Yeyeodu, S, et al, (2013) IRAK4 and TLR3 sequence variants may alter breast cancer risk among African-American women. Frontiers in Immunology, 4(338).

Research Objectives

Sean Kimbro has identified variants in innate immune genes common in people with African ancestry that may lead to higher breast and prostate cancer deaths.

Funding

NIH R01MD017405

Collaborators

• Dr Hernan Navarro
• Dr Kevin Williams

Bio

Dr Sean Kimbro earned his Bachelor of Arts in biology from Washington University in St Louis, Missouri, and a PhD in molecular and microbiology from Indiana University, Bloomington, Indiana. He did his post-doctoral training at the Harvard University School of Medicine, National Institutes of Health, and National Institute of Environmental Health Sciences.

Contact

E: kkimbro@nccu.edu

The role of protective immune genes in cancer disparities