The Impact Of CD56neg NK Cells in the Pathogenesis of Endemic Burkitt Lymphoma
Lay Summary: Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in Africa. This cancer is treatable with chemotherapy, but the survival rate for African children is 50%, in contrast to 90% survival for American children. This could be due to two common childhood infections that are considered risk factors for eBL, namely malaria and Epstein-Barr virus (EBV). A healthy immune system is able to recognize and kill human cells that have become infected or have become cancer cells. The children who get eBL live in areas of Africa where they get several malaria infections each year. They also get infected with EBV when they are infants. We think that when these children are fighting malaria, their immune cells become unadapted so they are not as able to kill efficiently cells that are infected with EBV. Normally, EBV does not cause any illness in infants but EBV can cause normal B cells to become cancer cells. Endemic BL is a B cell cancer that is almost always infected with EBV. If the immune system has been weakened, then it’s more likely the person could develop cancer.
Project Goal: To determine why the immune system for children who get eBL is not protecting them. If we can determine which parts of the immune system are important for fighting eBL, then we can determine other therapies that can be given to improve survival for these children.
Project Update 2024: A healthy immune system has functional Natural Killer (NK) cells, characterized by the expression of CD56 and CD16 and which recognize and kill infected cells or tumor cells. However, we showed that children residing in areas with a high incidence of malaria infections have an accumulation of an atypical CD56negCD16pos NK cell subset and we found an even more dramatic increase for children who have been diagnosed with eBL (who also come from areas with high malaria infection rates). My previous work showed that these atypical NK cells were not able to directly kill tumor cells as normal NK cells do. Therefore, I chose to look at another way NK cells can kill tumor cells: ADCC (antibody-dependent cell cytotoxicity) which involves IgG antibodies. Under the auspices of my ALSF award, I investigated the CD56neg NK cells’ ADCC potency and found that even though these cells can perform ADCC (~19% responded), they were not as efficient as the CD56dim NK cells (~30% responded). Moreover, I found that some patient-derived eBL tumor cell lines were more permissive to direct cytotoxicity without involvement of rituximab and that these CD56neg cytotoxic-capable actions were not eBL restricted but also directed other types of pediatric cancer such as Hodgkin and non-Hodgkin lymphoma, rhabdomyosarcoma and nephroblastoma. Focusing on the transition from CD56dim to CD56neg NK cells, I was also able to observe that it is not hyper-activation that appears to trigger the loss of CD56 surface expression, as hypothesized originally. Contrary to expectations, I did not observe a correlation between cytokine/chemokine plasma signatures and the proportion of CD56neg NK cells in eBL patients who survived cancer. But I was able to detect IL12, IL18 cytokines, essentials for NK cell cytotoxicity function suggesting that the lack of CD56neg NK cell direct cytotoxicity was not due to a cytokine deficiency but instead, that CD56neg NK cells’ dysfunction seems to be intrinsic to how the NK cells adapted to persistent malaria exposure and/or cancer. The results from this award strongly suggest that some patients might not be able to respond to rituximab antibody-treatment because of the predominance of CD56neg cells within the NK cells compartment, regardless of the type of cancer they have. Another grant application is planned to assess the impact of the CD56neg NK cells on the clinical outcome of patients treated with antibody therapy as well as evaluating other pathways that could explain the transition of the NK cell phenotype from CD56dim to CD56neg NK cells.
