Universität zu Köln

Sackey, Benedict ORCID: 0000-0003-1016-7720 (2023). Elucidation of the Role of DNA-Damage Response Genes in the Tumor Microenvironment and Molecular Characterization of a “Tropical” Chronic Lymphocytic Leukemia Cohort. PhD thesis, Universität zu Köln.

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Abstract

In most human cancers such as diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), major genes of the DNA damage response (DDR) complex such as TP53, suffers inactivating mutations and dysregulation that impairs DNA repair processes and apoptotic machinery relevant for treatment. Despite the successes with Chemoimmunotherapy (CIT), many B-cells malignancies remain a major clinical challenge as therapy resistance account for 90% of cancer related fatalities. The tumor microenvironment (TME) is particularly culpable. Protumorigenic TME promotes complex crosstalk of tumor and stroma cells to facilitate tumor survival, proliferation, immune escape and metastasis. This study elucidated the role of DDR in TME interactions and characterized molecular signature of Ghanaian CLL cohort. Using shRNA to downregulate DDR genes in an ABC-subtype of DLBCL cell line we demonstrate that, functional TP53 and ATX (SMG-1) genes are critical for ADCP of DLBCL cells and that loss of TP53 and ATX in DLBCL induce resistance towards CIT by inhibition of macrophage effector functions through changes in formation/secretion of cellular secretome. Additionally, phagocytosis is significantly enhanced in ABC-DLBCL expressing high levels of PD-L1 and CD47 antigens when treated in vitro with CIT/anti-CD47, anti-PD-L1 or anti-PD1 combination. Particularly, CD47/Sirp-α blockade circumvent impaired ADCP due to TP53, ATX, KD providing a rational for incorporation of checkpoint inhibitors into current R-CHOP regimen for the management of TP53, ATX mutated, resistant/refractory ABC-DLBCL. Characterization of tropical African CLL showed females predominant incidence (51.1% vs 48.9%), lower median age of incidence (59yrs with 42.2% < 55yrs) compared to Western CLL which shows predominant males incidence (2:1) with a higher median age (71yrs, with 5-11% < 55yrs). Measurement of informative molecular markers showed 80% good prognosis by ZAP-70 and CD38 but 88.4% presentation at late clinical stage of disease, higher monotypic sIgM than dual IgM+/IgD+ (54.5% vs 34.1%) compared to predominant dual IgM+/IgD+ expression among European patients. These differences in CLL biology and clinical outcome may reflect interplay of genetic and environmental factors among racial groups in different geographical settings.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Sackey, Benedict UNSPECIFIED orcid.org/0000-0003-1016-7720 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-707679
Date:	16 August 2023
Language:	English
Faculty:	Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language DNA-Damage Response, Tumor Microenvironment, Phagocytosis English Chronic Lymphocytic Leukemia, Diffuse large B cell lymphoma treatment English
Date of oral exam:	13 June 2023
Referee:	Name Academic Title Schumacher, Björn Prof. Dr. Utermöhlen, Olaf Prof. Dr Nürnberg, Peter Prof. Dr
Funders:	DAAD-MoE Ghana
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70767