Thesis Panagiota Bouti

On 5 November 2024 Sanquin researcher Panagiota Bouti defended her thesis 'Shaping neutrophil responses against cancer: the role of integrin regulation' at the University of Amsterdam

Promotor: Prof TW Kuijpers MD PhD
Copromotor :HL Matlung PhD
Venue: Agnietenkapel, University of Amsterdam

Abstract

Neutrophils, the most abundant cell type in blood circulation, play a crucial role in immune defense against pathogens and malignant cells. Accounting for up to 70% of total leukocytes, neutrophils are continuously generated in large numbers in the bone marrow. Yet, they exhibit a short half-life, lasting up to 24-48 hours with a brief circulation of 8-10 hours in the bloodstream. This short lifespan is purposeful, as they serve as the first line of defense against pathogens, being recruited to infection sites to eliminate pathogens before inflammation occurs. Neutrophils deploy various defense mechanisms to eradicate pathogens, including phagocytosis, degranulation, production of reactive oxygen species (ROS) via the NADPH oxidase complex, and release of neutrophil extracellular traps (NETs) as a suicidal mechanism to trap and kill pathogens. Our investigations center on the regulation of the CD11b/CD18 integrin and its downstream signaling pathways, including the identification of interacting proteins such as SKAP2, to elucidate the molecular mechanisms underpinning neutrophil anti-tumor responses. Moreover, we explore strategies to enhance neutrophil cytotoxicity towards cancer cells by targeting inhibitory immunoreceptor interactions, such as the CD47-SIRPα and SIGLEC-5/14 pathways, which hold promise for improving antibody-dependent cellular cytotoxicity (ADCC). We also examine tumor cell evasion mechanisms, exemplified by resistance against neutrophil trogocytosis mediated by the exocyst complex, highlighting the intricate interplay between innate immunity and cancer cell survival. These findings underscore the critical role of CD11b/CD18 in modulating neutrophil effector functions and offer novel insights into enhancing anti-tumor immune responses and developing potential therapeutic strategies in cancer treatment.

Chapters

Chapter 1
General introduction

PART I: lntegrin regulation in neutrophil host defense
Chapter 2
β2 integrin signaling cascade in neutrophils: more than a single function abstract

Chapter 3
SKAP2 acts downstream of CD11b/CD18 and regulates neutrophil effector function abstract

PART II: Neutrophil cytotoxicity towards tumor cells: unleashing the brakes
Chapter 4
KINDLIN3-dependent CD11b/CD18-integrin activation is required for potentiation of neutrophil cytotoxicity by CD47-SIRPα checkpoint disruption abstract

Chapter 5
The sialic acid-SIGLEC axis limits neutrophil ADCC against solid tumors through regulation of the CD11b/CD18 integrin affinity abstract

Chapter 6
Cancer cells resist antibody-mediated destruction by neutrophils through activation of the exocyst complex abstract

Chapter 7
General discussion

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