The Natural Killer Cell's Role in Diffuse Large B-Cell Lymphoma
Authors: Sallan Lorin , Kiryakoza Morgan , Hanona Paul , Jairath Neil , Ezekwudo Daniel , Jaiyesimi Ishmael A. 
Published: December 2024

Background: Diffuse Large B Cell Lymphoma (DLBCL) is a high grade Non-Hodgkin lymphoma with various treatment pathways. Natural Killer (NK) cells may pose a significant role in clinical outcomes for patients with DLBCL. They act by producing cytokines to limit tumor growth, and chemokines to lyse transformed cells. The role of NK cell and T cell concentration is known to alter disease processes by way of its tumor microenvironment. There is a relationship between the presence of activated NK cells in the tumor microenvironment and survival length, which can be studied further and play a role in immunotherapy.

Methods: DLBCL RNA sequencing data was extracted from The Cancer Genome Atlas (TCGA) (n=48). CIBERSORT identified immune cell fractions present in each patient sample, while Radiant by Shiny was utilized to extrapolate the linear regression between overall survival and each cell line. This included B-cells Memory, Plasma cells, CD8 T-cells, CD-4 T cells (memory resting, memory activated, follicular helper, regulatory, gamma delta), NK cells resting, NK cells activated, Monocytes, macrophages (M0, M1, M2), dendritic cells activated, mast cells (resting, activated), eosinophils,and neutrophils.

Results: Activated natural killer cells were analyzed by linear regression and independently associated with overall survival by multivariable analysis (p=0.023) with a correlation coefficient of +2251.136 indicating a positive relationship between activated NK cells and overall survival in DLBCL.

Conclusions: The presence and quantity of NK cells in the DLBCL tumor microenvironment had longer overall survival. This finding is not only specific to DLBCL, it has also been demonstrated in colorectal, renal and some squamous cell cancers that the density of NK cells is positively associated with the overall survival length as well as disease-free survival. The lower density of NK cells is associated with shorter survival rates, and may signify the lack of immune response to tumor cells. NK cell maturation occurs in the bone marrow and lymphoid tissue, and may be affected by the lymphoma cells. Cellular toxicity by NK cells has potential for targeting specific antigens on cancer cells by genetic modification. This would minimize side effects while optimizing the eradication of pathologic cells. The production of cytokines such as IL-7 and IL-2 may support the viability of NK cells to create a microenvironment that can prolong survival and possibly improve cell signaling to the pathologic tumor cells. CAR-T therapy may play a substantial role in NK cellular immunotherapy as T cells and NK cells both participate in cell signaling. Some studies even show that in contrast to T cells, NK cells may have a more favorable side effect profile when used as immunotherapy. This increasing affinity of NK cells to tumor cells is a potential for therapy but not without risks of side effects, including the potential emergence of treatment resistant tumor cells. The tumor microenvironment has much to be understood in the role of overall survival, and may play a large role in immunotherapy in the future.