Role of Innate Immune Checkpoint in Drug Mediated Phagocytosis in B-cell Lymphoma
Open AccessThe lymphatic organ system is responsible for helping the human body in fighting pathogens by circulating white blood cells to areas of infection. There are many types of cancers of the lymphatic system which divide into the two categories of non-Hodgkin’s (NHL) and Hodgkin’s lymphoma (HL). The main two differences between these two lymphomas is that HL is associated by the presence of Reed Sternberg Cells and occur in the young and adolescent patients, however NHL is more common than HL and occurs in adult patients. NHL can occur in B cells or T cells. In B-cells there are several subtypes of lymphoma including Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL). The primary focus of this study will be on MCL. MCL can occur as a result of the malignant transformation of B lymphocytes in the outer edge of the lymph node follicle, what is known as the mantle zone. This transformed B lymphocyte can then grow and proliferate uncontrollably, resulting in the enlargement of the lymph nodes. These B lymphomas can then enter the lymphatic channels and then the blood to circulate around different tissues in the body and metastasize. When the human body is exposed to a new pathogen or virus, the innate immune system is activated during the first hours or days of exposure. This defense system utilizes the use of Basophils, Neutrophils, Natural Killer (NK) Cells, and Macrophages to dispose the new/unknown pathogen. Through phagocytosis, the process of engulfing a foreign antigen, these macrophages kill any new pathogens present in the body. However, in order to make sure these defense cells do not attack the normal cells of the body, a process called autoimmunity, the innate immune system has utilized checkpoints to serve as stop signs. These innate immune checkpoints help protect the normal cells from being attacked by the body’s defense mechanism. Cancer cells have used these innate immune checkpoints to their advantage to evade killing and thus proliferate. MCL has been one of the emerging NHL cancer types with its involvement in innate immune checkpoint CD47/SIRP-⍺. Macrophages should be able to engulf and phagocytose the cancer cells; however, B-cell lymphomas have developed a way to express the "don't eat me" protein Cluster of Differentiation 47 (CD47) on their surface to evade phagocytosis. CD47 is a receptor protein on the surface of normal B lymphocytes which acts as a “don’t eat me” signal for macrophages. Signal Regulatory Protein ⍺ (SIRP-⍺) is the immunoreceptor of macrophages that interacts with CD47 and prevents these circulatory macrophages from killing the cells. B lymphocytes have developed a way to increase the expression of CD47 on their surface to evade phagocytosis. However, the expression of SIRP-⍺ on macrophages as well as the phagocytic activity of M1 and M2 macrophages is not well known. With the use of flow cytometry and co-culture techniques it is evident that M1 has higher phagocytic activity than M2. The role of innate immune checkpoint is not well understood in lymphomas, specifically in MCL and B lymphocytes. Through the use of targeted therapy drugs in combination with immunotherapy and checkpoint inhibitors such as ibrutinib and lenalidomide, the efficacy of phagocytosis can be better understood. These findings all together highlight the importance of innate immune checkpoints such as CD47/SIRP-⍺ and their role in the tumor immune response and how they might serve as a potential therapeutic target for B-cell malignancies. Targeting these checkpoints through the use of combination drug therapy can deem more effective in treating patients and possibly pave the way for better clinical studies.
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Ghaemmaghami_gwu_0075M_15646.pdf | 2022-03-06 | Open Access |
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